403 results on '"Fernando C Fervenza"'
Search Results
2. Membranous Nephropathy: Current Understanding in The Light of New Advances
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Hakan Özer, Ismail Baloğlu, Fernando C Fervenza, and Kultigin Türkmen
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Internal medicine ,RC31-1245 ,Pediatrics ,RJ1-570 - Published
- 2023
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3. Risk of relapse of ANCA-associated vasculitis among patients homozygous for the proteinase 3 gene Val119Ile polymorphism
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John H Stone, Peter C Grayson, Ulrich Specks, E William St Clair, Peter A Merkel, Philip Seo, Carol A Langford, Paul A Monach, Cees G M Kallenberg, Robert F Spiera, Fernando C Fervenza, Zuoming Deng, Wei Tew, Marta Casal Moura, Stephen R Brooks, and Marco Prunotto
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Medicine - Abstract
Background The frequency of proteinase 3 gene (PRTN3) polymorphisms in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is not fully characterised. We hypothesise that the presence of a PRTN3 gene polymorphism (single nucleotide polymorphism (SNP) rs351111) is relevant for clinical outcomes.Methods DNA variant calling for SNP rs351111 (chr.19:844020, c.355G>A) in PRTN3 gene assessed the allelic frequency in patients with PR3-AAV included in the Rituximab in ANCA-Associated Vasculitis trial. This was followed by RNA-seq variant calling to characterise the mRNA expression. We compared clinical outcomes between patients homozygous for PRTN3-Ile119 or PRTN3-Val119.Results Whole blood samples for DNA calling were available in 188 patients. 75 patients with PR3-AAV had the allelic variant: 62 heterozygous PRTN3-Val119Ile and 13 homozygous for PRTN3-Ile119. RNA-seq was available for 89 patients and mRNA corresponding to the allelic variant was found in 32 patients with PR3-AAV: 25 heterozygous PRTN3-Val119Ile and 7 homozygous for PRTN3-Ile119. The agreement between the DNA calling results and mRNA expression of the 86 patients analysed by both methods was 100%. We compared the clinical outcomes of 64 patients with PR3-AAV: 51 homozygous for PRTN3-Val119 and 13 homozygous for PRTN3-Ile119. The frequency of severe flares at 18 months in homozygous PRTN3-Ile119 was significantly higher when compared with homozygous PRTN3-Val119 (46.2% vs 19.6%, p=0.048). Multivariate analysis identified homozygous PR3-Ile119 as main predictor of severe relapse (HR 4.67, 95% CI 1.16 to 18.86, p=0.030).Conclusion In patients with PR3-AAV, homozygosity for PRTN3-Val119Ile polymorphism appears associated with higher frequency of severe relapse. Further studies are necessary to better understand the association of this observation with the risk of severe relapse.
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- 2023
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4. Safety and efficacy of enzyme replacement therapy in the nephropathy of Fabry disease
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Fernando C Fervenza, Roser Torra, and David G Warnock
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Medicine (General) ,R5-920 - Abstract
Fernando C Fervenza1, Roser Torra2, David G Warnock31Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, MN, USA; 2Department of Nephrology, Fundació Puigvert, Barcelona, Spain; 3Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL, USAAbstract: Kidney involvement with progressive loss of kidney function (Fabry nephropathy) is an important complication of Fabry disease, an X-linked lysosomal storage disorder arising from deficiency of α-galactosidase activity. Clinical trials have shown that enzyme replacement therapy (ERT) with recombinant human α-galactosidase clears globotriaosylceramide from kidney cells, and can stabilize kidney function in patients with mild to moderate Fabry nephropathy. Recent trials show that patients with more advanced Fabry nephropathy and overt proteinuria do not respond as well to ERT alone, but can benefit from anti-proteinuric therapy given in conjunction with ERT. This review focuses on the use of enzyme replacement therapy with agalsidase-alfa and agalsidase-beta in adults with Fabry nephropathy. The current results are reviewed and evaluated. The issues of dosing of enzyme replacement therapy, the use of adjunctive agents to control urinary protein excretion, and the individual factors that affect disease severity are reviewed.Keywords: agalsidase, enzyme replacement therapy, Fabry nephropathy, anti-proteinuric therapy
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- 2008
5. Longitudinal Changes in Health-Related Quality of Life in Primary Glomerular Disease: Results From the CureGN Study
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Shannon L. Murphy, John D. Mahan, Jonathan P. Troost, Tarak Srivastava, Amy J. Kogon, Yi Cai, T. Keefe Davis, Hilda Fernandez, Alessia Fornoni, Rasheed A. Gbadegesin, Emily Herreshoff, Pietro A. Canetta, Patrick H. Nachman, Bryce B. Reeve, David T. Selewski, Christine B. Sethna, Chia-shi Wang, Sharon M. Bartosh, Debbie S. Gipson, Katherine R. Tuttle, Ali Gharavi, Wooin Ahn, Gerald B. Appel, Rupali S. Avasare, Revekka Babayev, Ibrahim Batal, Andrew S. Bomback, Eric Brown, Eric S. Campenot, Pietro Canetta, Brenda Chan, Vivette D. D’Agati, Bartosz Foroncewicz, Gian Marco Ghiggeri, William H. Hines, Namrata G. Jain, Krzysztof Kiryluk, Fangming Lin, Francesca Lugani, Maddalena Marasa, Glen Markowitz, Sumit Mohan, Krzysztof Mucha, Thomas L. Nickolas, Jai Radhakrishnan, Maya K. Rao, Renu Regunathan-Shenk, Simone Sanna-Cherchi, Dominick Santoriello, Michael B. Stokes, Natalie Yu, Anthony M. Valeri, Ronald Zviti, Larry A. Greenbaum, William E. Smoyer, Amira Al-Uzri, Isa Ashoor, Diego Aviles, Rossana Baracco, John Barcia, Sharon Bartosh, Craig Belsha, Michael C. Braun, Aftab Chishti, Donna Claes, Carl Cramer, Keefe Davis, Elif Erkan, Daniel Feig, Michael Freundlich, Melisha Hanna, Guillermo Hidalgo, Amrish Jain, Myda Khalid, Mahmoud Kallash, MD, Jerome C. Lane, John Mahan, Nisha Mathews, Carla Nester, Cynthia Pan, Hiren Patel, Adelaide Revell, Rajasree Sreedharan, Julia Steinke, Scott E. Wenderfer, Craig S. Wong, Ronald Falk, William Cook, Vimal Derebail, Agnes Fogo, Adil Gasim, Todd Gehr, Raymond Harris, Jason Kidd, Louis-Philippe Laurin, Will Pendergraft, Vincent Pichette, Thomas Brian Powell, Matthew B. Renfrow, Virginie Royal, Lawrence B. Holzman, Sharon Adler, Charles Alpers, Raed Bou Matar, Elizabeth Brown, Michael Choi, Katherine M. Dell, Ram Dukkipati, Fernando C. Fervenza, Crystal Gadegbeku, Patrick Gipson, Leah Hasely, Sangeeta Hingorani, Michelle A. Hladunewich, Jonathan Hogan, J. Ashley Jefferson, Kenar Jhaveri, Duncan B. Johnstone, Frederick Kaskel, Amy Kogan, Jeffrey Kopp, Kevin V. Lemley, Laura Malaga- Dieguez, Kevin Meyers, Alicia Neu, Michelle Marie O'Shaughnessy, John F. O’Toole, Rulan Parekh, Heather Reich, Kimberly Reidy, Helbert Rondon, Kamalanathan K. Sambandam, John R. Sedor, Jeffrey Schelling, John C. Sperati, Agnes Swiatecka-Urban, Howard Trachtman, Joseph Weisstuch, Olga Zhdanova, Brenda Gillespie, Matthias Kretzler, Bruce M. Robinson, Laura Mariani, Matthew Wladkowski, and Lisa M. Guay-Woodford
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edema ,health-related quality of life ,patient-reported outcomes ,primary glomerular disease ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Introduction: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. Methods: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. Results: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. Conclusion: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.
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- 2020
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6. Nonrecurrent Early Post-Transplantation Focal Segmental Glomerulosclerosis
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Momina M. Ahmed, Massini A. Merzkani, Matthew R. D’Costa, Muhannad A. Leghrouz, Mary E. Fidler, Haraldur Bjarnason, Patrick G. Dean, Fernando C. Fervenza, Sanjit Reddy, and Hatem Amer
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Diseases of the genitourinary system. Urology ,RC870-923 - Published
- 2020
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7. Nail-patella-like renal disease masquerading as Fabry disease on kidney biopsy: a case report
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Filippo Pinto e Vairo, Pavel N. Pichurin, Fernando C. Fervenza, Samih H. Nasr, Kevin Mills, Christopher T. Schmitz, Eric W. Klee, and Sandra M. Herrmann
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Fabry disease ,LMX1B ,Nail-patella-like renal disease ,Individualized medicine ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Abstract Background Genetic changes in the LIM homeobox transcription factor 1 beta (LMX1B) have been associated with focal segmental glomerulosclerosis (FSGS) without the extra-renal or ultrastructural manifestations of Nail-patella syndrome (NPS) known as Nail-patella-like renal disease (NPLRD). Fabry disease (FD) is an X-linked lysosomal disease caused by the deficiency of alpha-galactosidase A. The classic form of the disease is characterized by acroparesthesia, angiokeratomas, cornea verticillata, hypertrophic cardiomyopathy, strokes, and chronic kidney disease. Podocyte myelin bodies on ultrastructural examination of kidney tissue are very characteristic of FD; however some medications and other conditions may mimic this finding. Case presentation Here, we report on a female patient with chronic kidney disease (CKD), positive family history for kidney disease and kidney biopsy showing a FSGS lesion and presence of focal myelin figures within podocytes concerning for FD. However, genetic testing for FD was negative. After comprehensive clinical, biochemical, and genetic evaluation, including whole exome and RNA sequencing, she was ultimately diagnosed with NPLRD. Conclusions This case illustrates the difficulties of diagnosing atypical forms of rare Mendelian kidney diseases and the role of a multidisciplinary team in an individualized medicine clinic setting in combination with state-of-the-art sequencing technologies to reach a definitive diagnosis.
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- 2020
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8. Proteomic Analysis of Complement Proteins in Membranous Nephropathy
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Aishwarya Ravindran, Benjamin Madden, M. Cristine Charlesworth, Rishi Sharma, Amit Sethi, Hanna Debiec, Daniel Cattran, Fernando C. Fervenza, Richard J. Smith, Pierre Ronco, and Sanjeev Sethi
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)– and exostosin 1 (EXT1)/exostosin 2 (EXT2)–associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN. Methods: We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated (n = 7), EXT1/EXT2-associated MN (n = 21), and 11 control cases (time 0 transplant biopsies). Results: MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R- and EXT1/EXT2-positive MN. Both PLA2R- and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R- and EXT1/EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN. Conclusion: Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3- and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN. Keywords: complement, laser microdissection, mass spectrometry, membranous nephropathy
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- 2020
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9. An Open-Label Pilot Study of Adrenocorticotrophic Hormone in the Treatment of IgA Nephropathy at High Risk of Progression
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Ladan Zand, Pietro Canetta, Richard Lafayette, Nabeel Aslam, Novak Jan, Sanjeev Sethi, and Fernando C. Fervenza
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Introduction: IgA nephropathy (IgAN) is the most common glomerulonephritis with high risk of progression to end-stage renal disease in patients with proteinuria >1 g/24 hours. There are no known effective treatments in patients with IgAN. Methods: We conducted a prospective open-label pilot study in patients with IgAN using adrenocorticotrophic hormone (ACTH) (Acthar Gel, Mallinckrodt Pharmaceuticals, Bedminster, NJ) at a dosage of 80 units subcutaneously twice weekly for a total of 6 months and followed patients for a total of 12 months. Patients had to have urinary protein >1 g/24 hours despite adequate renin-angiotensin-aldosterone system (RAAS) blockade and estimated glomerular filtration rate (eGFR) >30 ml/min at enrollment. Results: A total of 19 patients were recruited and followed for 1 year. At baseline, the mean age was 34.9 ± 10.5 years with 11 men and 8 women, and 14 Caucasian and 5 Asian individuals. At 12 months, there was a statistically significant decline in 24-hour urinary protein from 2.6 to 1.3 g (P = 0.007) and significant increase in serum albumin (3.79 to 3.93, P = 0.02). There was no significant change in eGFR (65.5 to 61.1 ml/min, P = 0.1). There were 0 complete remissions and 8 partial remissions (42%). There were a total of 6 infections: 2 were viral and 4 required antibiotic therapy (2 sinusitis, 1 pneumonia, 1 otitis media). The most common adverse events included acne, hot flashes, soreness, and anxiety. Conclusion: In summary, patients with IgAN with >1 g/24-hour urinary protein and eGFR >30 ml/min had a significant reduction in 24-hour urinary protein with stable eGFR at 12-month follow-up after being treated with 6 months of ACTH. Keywords: ACTH, IgA nephropathy, proteinuria
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- 2020
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10. C3 Glomerulonephritis: A Rare Etiology of the Pulmonary Renal Syndrome
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Shane A. Bobart, Sanjeev Sethi, and Fernando C. Fervenza
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
C3 Glomerulopathy is a rare form of kidney disease due to dysregulation of the alternative complement pathway. We report a case of a college-aged woman with C3 glomerulonephritis (C3GN), presenting with the unexpected extrarenal manifestation of pulmonary hemorrhage. The patient presented with a nephritic urinary sediment and acute kidney injury after a recent infection. Kidney biopsy demonstrated focal endocapillary proliferative, crescentic, and necrotizing glomerulonephritis with bright glomerular C3 staining only. Electron microscopy revealed mesangial, intramembranous, and subendothelial deposits. After 2 doses of intravenous methylprednisolone, the patient developed spontaneous hemoptysis and respiratory compromise requiring emergent intubation. Bronchoscopy and computed tomography findings were consistent with diffuse alveolar hemorrhage. Notable laboratory results included C3, 40 (reference range, 75-175) mg/dL, and negative antinuclear antibody, antineutrophil cytoplasmic antibody, and anti–glomerular basement membrane serology results. As an outpatient, genetic testing revealed the presence of C3 glomerulopathy risk alleles. A diagnosis of C3GN complicated by pulmonary hemorrhage was made. There was initial response to treatment with steroids and mycophenolate mofetil; however, after repeated relapses of proteinuria and hematuria, treatment with eculizumab showed an initial response, but the patient subsequently became hemodialysis dependent. Our case highlights that C3GN can present with crescents and have other extrarenal manifestations such as pulmonary hemorrhage and should also be considered part of the differential diagnosis in patients presenting with pulmonary renal syndrome. Index Words: C3 Glomerulonephritis, pulmonary hemorrhage, complement pathway
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- 2019
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11. Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
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Alvise Berti, Sophie Hillion, Maximilian F. Konig, Marta Casal Moura, Amber M. Hummel, Eva Carmona, Tobias Peikert, Fernando C. Fervenza, Cees G.M. Kallenberg, Carol A. Langford, Peter A. Merkel, Paul A. Monach, Philip Seo, Robert F. Spiera, Paul Brunetta, E. William St. Clair, Kristina M. Harris, John H. Stone, Guido Grandi, Jacques‐Olivier Pers, Ulrich Specks, and Divi Cornec
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Rheumatology ,Immunology ,Immunology and Allergy - Published
- 2023
12. Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3
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Marta Casal, Moura, Gwen E, Thompson, Darlene R, Nelson, Lynn A, Fussner, Amber M, Hummel, Dieter E, Jenne, Daniel, Emerling, Fernando C, Fervenza, Cees G M, Kallenberg, Carol A, Langford, W Joseph, McCune, Peter A, Merkel, Paul A, Monach, Philip, Seo, Robert F, Spiera, E William, St Clair, Steven R, Ytterberg, John H, Stone, William H, Robinson, and Ulrich, Specks
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Rheumatology ,Immunology ,Immunology and Allergy - Abstract
Proteinase 3 (PR3) is the major antigen for anti-neutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3 anti-neutrophil cytoplasmic antibodies (PR3-ANCAs) recognize different epitopes on PR3. We aimed to study the effect of mutations on PR3 antigenicity.The recombinant PR3 variants, iPR3 (clinically used to detect PR3-ANCAs) and iHm5 (containing three point mutations in Epitope 15 generated for epitope mapping studies, immunoassays and serum samples from patients enrolled in ANCA-associated vasculitis (AAV) trials were used to screen the differential PR3-ANCA binding. A patient-derived monoclonal ANCA (moANCA518) that selectively binds to iHm5 within the mutation-free Epitope 3 and distant from the point mutations of iHm5 was used as a gauge of remote epitope activation. Selective binding was determined by inhibition experiments.Rather than reduced binding of PR3-ANCAs to iHm5, we found substantially increased binding of the majority of PR3-ANCAs to iHm5 compared with iPR3. This differential binding of PR3-ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3-2 also induced recognition by moANCA518.The preferential binding of PR3-ANCAs from patients like the selective binding of moANCA518 to iHm5 is conferred by increased antigenicity of Epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR-2. This previously unrecognized characteristic of PR3-ANCA interactions with its target antigen has implications for studying antibody-mediated autoimmune diseases, understanding of variable performance characteristics of immunoassays and design of potential novel treatment approaches. This article is protected by copyright. All rights reserved.
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- 2023
13. Novel Treatments Paradigms: Membranous Nephropathy
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Jorge E. Rojas-Rivera, Alberto Ortiz, and Fernando C. Fervenza
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Nephrology - Published
- 2023
14. Overlap of C3 Glomerulopathy and Thrombotic Microangiopathy: A Case Series
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Aishwarya Ravindran, Lilian Monteiro Pereira Palma, Fernando C. Fervenza, and Sanjeev Sethi
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Nephrology - Published
- 2023
15. Incidence, Prevalence, and Mortality of Lupus Nephritis: A <scp>Population‐Based</scp> Study Over Four Decades Using the Lupus Midwest Network
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Mehmet Hocaoǧlu, Maria O. Valenzuela‐Almada, Jesse Y. Dabit, Shirley‐Ann Osei‐Onomah, Baptiste Chevet, Rachel E. Giblon, Ladan Zand, Fernando C. Fervenza, Charles G. Helmick, Cynthia S. Crowson, and Alí Duarte‐García
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Rheumatology ,Immunology ,Immunology and Allergy - Published
- 2023
16. Complement gene variant effect on relapse of complement-mediated thrombotic microangiopathy after eculizumab cessation
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Aldo A. Acosta-Medina, Ann M. Moyer, Ronald S. Go, Maria Alice V. Willrich, Fernando C. Fervenza, Nelson Leung, Christianne Bourlon, Jeffrey L. Winters, Grant M. Spears, Sandra C. Bryant, and Meera Sridharan
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Hematology - Abstract
Eculizumab is effective for complement-mediated thrombotic microangiopathy (CM-TMA), also known as atypical hemolytic uremic syndrome. Although lifelong therapy had been suggested, discontinuation does not universally lead to relapse. Comprehensive data evaluating risk factors for recurrence following discontinuation are limited. Our aim was to systematically review available literature assessing the role of complement genetic variants in this setting. Reports on CM-TMA and eculizumab withdrawal published before 1 January 2021, were included. Key reasons for patient exclusion were no follow-up after drug withdrawal and patients lacking complement genetic testing. Two-hundred eighty patients from 40 publications were included. Median age was 28 years, and 25 patients had a known history of renal transplant. Complement genetic variants were identified in 60%, most commonly in CFH (n = 59) and MCP/CD46 (n = 38). Of patients with a complement gene variant, 51.3% had ≥1 likely pathogenic/pathogenic variant whereas the remaining had variants of uncertain significance (VUS). Overall relapse rate after therapy discontinuation was 29.6%. Relapse rate was highest among patients with CFH variants and MCP/CD46 variants in canonical splice regions. VUS (P < .001) and likely pathogenic/pathogenic variants (P < .001) were associated with increased relapse. Presence of a renal allograft (P = .009); decreasing age (P = .029); and detection of variants in CFH (P < .001), MCP/CD46 (P < .001), or C3 (P < .001) were all independently associated with relapse after eculizumab discontinuation. Eculizumab discontinuation is appropriate in specific patients with CM-TMA. Caution should be exerted when attempting such a strategy in patients with high risk of recurrence, including a subgroup of patients with MCP/CD46 variants.
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- 2023
17. Membranous Nephropathy in Syphilis is Associated with Neuron-Derived Neurotrophic Factor
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Sanjeev Sethi, Benjamin Madden, Marta Casal Moura, Raman Deep Singh, Samih H. Nasr, Jean Hou, Alok Sharma, Karl A. Nath, Ulrich Specks, Fernando C. Fervenza, and Mark Haas
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Nephrology ,General Medicine - Published
- 2023
18. Maintenance of Remission and Risk of Relapse in Myeloperoxidase-Positive ANCA-Associated Vasculitis with Kidney Involvement
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Marta Casal Moura, Ulrich Specks, Shahrzad Tehranian, Sanjeev Sethi, Dalia Zubidat, Luca Nardelli, Fernanda G. dos Santos, Ciria Sousa, Juan León-Róman, Shane A. Bobart, Eddie Greene, Ladan Zand, and Fernando C. Fervenza
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Transplantation ,Nephrology ,Epidemiology ,Critical Care and Intensive Care Medicine - Published
- 2023
19. Diagnosing and treating ANCA-associated vasculitis: an updated review for clinical practice
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Baptiste Chevet, Divi Cornec, Marta Casal Moura, Emilie Cornec-Le Gall, Fernando C Fervenza, Kenneth J Warrington, Ulrich Specks, and Alvise Berti
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Rheumatology ,Pharmacology (medical) - Abstract
ANCA-associated vasculitides (AAV) are a group of rare, primary, systemic necrotizing small-vessel vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis account for ∼80–90% of all AAV. Exposure to silica dust, farming and chronic nasal Staphylococcus aureus carriage are associated with increased risk of developing AAV. When a diagnosis of AAV is suspected, as in patients with multisystem organ dysfunction or those with features such as chronic recurrent rhinosinusitis, cavitated lung nodules, palpable purpura or acute kidney injury, then appropriate further investigations are needed, including ANCA testing. In this scenario, a structured clinical assessment should be conducted, evaluating all the organs possibly involved, and tissue biopsy may be necessary for confirmation of the diagnosis. Therapeutic algorithms vary based on the severity of AAV, the clinical diagnosis/ANCA specificity, and the patient’s age, weight, comorbidities and prognosis. Recent data favour rituximab as a preferable option for both induction and maintenance of remission. In addition, regimens with less glucocorticoids are equally effective and safer in inducing remission compared with conventional regimens, and avacopan is an effective glucocorticoid-sparing option. In contrast, there is not compelling evidence to support the routine use of plasma exchange in addition to standard remission-induction therapy in AAV. ANCA and other biomarkers can be helpful in association with clinical assessment to guide diagnosis and treatment decisions. Patients should be frequently evaluated during follow-up for possible disease relapses or treatment-related morbidity, and for monitoring damage accrual, especially metabolic and cardiovascular damage.
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- 2022
20. PLEX in AAV-GN: insights from the meta-analysis results and impact on remission induction treatment recommendations
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Marta Casal Moura, Cynthia S Crowson, Ulrich Specks, Kenneth J Warrington, Ladan Zand, Sanjeev Sethi, and Fernando C Fervenza
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Transplantation ,Nephrology - Abstract
The risk of progression to end-stage kidney disease (ESKD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and glomerulonephritis (AAV-GN) remains high. At 5 years of follow-up, 14–25% of patients will evolve to ESKD, suggesting that kidney survival is not optimized in patients with AAV. The addition of plasma exchange (PLEX) to standard remission induction has been the standard of care, particularly in patients with severe renal disease. However, there is still some debate regarding which patients benefit from PLEX. A recently published meta-analysis concluded that the addition of PLEX to standard remission induction in AAV probably reduced the risk of ESKD at 12 months and that PLEX was associated with an estimated absolute risk reduction for ESKD at 12 months of 16.0% for those at high risk or with a serum creatinine >5.7 mg/dl (high certainty of important effects). These findings were interpreted as supportive of offering PLEX to patients with AAV and a high risk of progression to ESKD or requiring dialysis and are making their way into societies recommendations. However, the results of the analysis can be debated. We provide an overview on the meta-analysis as an attempt to guide the audience through how the data were generated, to comment on our interpretation of the results and to explain why we feel uncertainty remains. In addition, we would like to provide insights in two questions that we believe are very relevant to consider when addressing the role of PLEX: the role of kidney biopsy findings in the decision making of whom might benefit from PLEX and the impact of novel treatments (i.e. complement factor 5a inhibitors) in avoiding progression to ESKD at 12 months. The treatment of patients with severe AAV-GN is complex and further studies that include only patients at high risk of progression to ESKD are needed.
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- 2022
21. Prognostic Implications of a Morphometric Evaluation for Chronic Changes on All Diagnostic Native Kidney Biopsies
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Aleksandar Denic, Marija Bogojevic, Aidan F. Mullan, Moldovan Sabov, Muhammad S. Asghar, Sanjeev Sethi, Maxwell L. Smith, Fernando C. Fervenza, Richard J. Glassock, Musab S. Hommos, and Andrew D. Rule
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Nephrology ,General Medicine - Abstract
Semiquantitative visual inspection for glomerulosclerosis, interstitial fibrosis, and arteriosclerosis is often used to assess chronic changes in native kidney biopsies. Morphometric evaluation of these and other chronic changes may improve the prognostic assessment.We studied a historical cohort of patients who underwent a native kidney biopsy between 1993 and 2015 and were followed through 2021 for ESKD and for progressive CKD (defined as experiencing 50% eGFR decline, temporary dialysis, or ESKD). Pathologist scores for the percentages of globally sclerosed glomeruli (GSG), interstitial fibrosis and tubular atrophy (IFTA), and arteriosclerosis (luminal stenosis) were available. We scanned biopsy sections into high-resolution images to trace microstructures. Morphometry measures were percentage of GSG; percentage of glomerulosclerosis (percentage of GSG, ischemic-appearing glomeruli, or segmentally sclerosed glomeruli); percentage of IFTA; IFTA foci density; percentage of artery luminal stenosis; arteriolar hyalinosis counts; and measures of nephron size. Models assessed risk of ESKD or progressive CKD with biopsy measures adjusted for age, hypertension, diabetes, body mass index, eGFR, and proteinuria.Of 353 patients (followed for a median 7.5 years), 75 developed ESKD and 139 experienced progressive CKD events. Visually estimated scores by pathologists versus morphometry measures for percentages of GSG, IFTA, and luminal stenosis did not substantively differ in predicting outcomes. However, adding percentage of glomerulosclerosis, IFTA foci density, and arteriolar hyalinosis improved outcome prediction. A 10-point score using percentage of glomerulosclerosis, percentage of IFTA, IFTA foci density, and any arteriolar hyalinosis outperformed a 10-point score based on percentages of GSG, IFTA, and luminal stenosis50% in discriminating risk of ESKD or progressive CKD.Morphometric characterization of glomerulosclerosis, IFTA, and arteriolar hyalinosis on kidney biopsy improves prediction of long-term kidney outcomes.
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- 2022
22. DNAJB9 Is a Specific Immunohistochemical Marker for Fibrillary Glomerulonephritis
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Samih H. Nasr, Julie A. Vrana, Surendra Dasari, Frank Bridoux, Mary E. Fidler, Sihem Kaaki, Nathalie Quellard, Alexia Rinsant, Jean Michel Goujon, Sanjeev Sethi, Fernando C. Fervenza, Lynn D. Cornell, Samar M. Said, Ellen D. McPhail, Loren P. Herrera Hernandez, Joseph P. Grande, Marie C. Hogan, John C. Lieske, Nelson Leung, Paul J. Kurtin, and Mariam P. Alexander
- Subjects
biomarker ,DNAJB9 ,fibrillary glomerulonephritis ,immunoelectron microscopy ,immunohistochemistry ,kidney biopsy ,Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Fibrillary glomerulonephritis (FGN) is a rare disease with unknown pathogenesis and a poor prognosis. Until now, the diagnosis of this disease has required demonstration of glomerular deposition of randomly oriented fibrils by electron microscopy that are Congo red negative and stain with antisera to Igs. We recently discovered a novel proteomic tissue biomarker for FGN, namely, DNAJB9. Methods: In this work, we developed DNAJB9 immunohistochemistry and tested its sensitivity and specificity for the diagnosis of FGN. This testing was performed on renal biopsy samples from patients with FGN (n = 84), amyloidosis (n = 21), a wide variety of non-FGN glomerular diseases (n = 98), and healthy subjects (n = 11). We also performed immunoelectron microscopy to determine whether DNAJB9 is localized to FGN fibrils. Results: Strong, homogeneous, smudgy DNAJB9 staining of glomerular deposits was seen in all but 2 cases of FGN. The 2 cases that did not stain for DNAJB9 were unique, as they had glomerular staining for IgG only (without κ or λ) on immunofluorescence. DNAJB9 staining was not observed in cases of amyloidosis, in healthy subjects, or in non-FGN glomerular diseases (with the exception of very focal staining in 1 case of smoking-related glomerulopathy), indicating 98% sensitivity and > 99% specificity. Immunoelectron microscopy showed localization of DNAJB9 to FGN fibrils but not to amyloid fibrils or immunotactoid glomerulopathy microtubules. Conclusion: DNAJB9 immunohistochemistry is sensitive and specific for FGN. Incorporation of this novel immunohistochemical biomarker into clinical practice will now allow more rapid and accurate diagnosis of this disease.
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- 2018
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23. Atypical Antiglomerular Basement Membrane Nephritis Following Immune Checkpoint Inhibitor
- Author
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Vincent Javaugue, Myra J. Watson, Fernando C. Fervenza, and Samih H. Nasr
- Subjects
Nephrology - Published
- 2022
24. Association of Histologic Parameters with Outcome in C3 Glomerulopathy and Idiopathic Immunoglobulin-Associated Membranoproliferative Glomerulonephritis
- Author
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Hannah J. Lomax-Browne, Nicholas R. Medjeral-Thomas, Sean J. Barbour, Jack Gisby, Heedeok Han, Andrew S. Bomback, Fernando C. Fervenza, Thomas H. Cairns, Richard Szydlo, Sven-Jean Tan, Stephen D. Marks, Aoife M. Waters, Gerald B. Appel, Vivette D. D’Agati, Sanjeev Sethi, Cynthia C. Nast, Ingeborg Bajema, Charles E. Alpers, Agnes B. Fogo, Christoph Licht, Fadi Fakhouri, Daniel C. Cattran, James E. Peters, H. Terence Cook, and Matthew C. Pickering
- Subjects
Transplantation ,Glomerulonephritis, Membranoproliferative ,Epidemiology ,Biopsy ,membranoproliferative glomerulonephritis (MPGN) ,kidney biopsy ,Immunoglobulins ,Complement C3 ,Critical Care and Intensive Care Medicine ,Fibrosis ,Proteinuria ,Editorial ,Nephrology ,Humans ,Original Article ,Kidney Diseases ,complement ,Renal Insufficiency ,Atrophy ,glomerulonephritis ,Retrospective Studies - Abstract
Background and objectives: C3 glomerulopathy and idiopathic Ig-associated membranoproliferative GN are kidney diseases characterized by abnormal glomerular complement C3 deposition. These conditions are heterogeneous in outcome, but approximately 50% of patients develop kidney failure within 10 years. Design, setting, participants, & measurements: To improve identification of patients with poor prognosis, we performed a detailed analysis of percutaneous kidney biopsies in a large cohort of patients. Using a validated histologic scoring system, we analyzed 156 native diagnostic kidney biopsies from a retrospective cohort of 123patients with C3 glomerulopathy and 33 patients with Ig-associated membranoproliferative GN. We used linear regression, survival analysis, and Cox proportional hazards models to assess the relationship between histologic and clinical parameters with outcome. Results: Frequent biopsy features were mesangial expansion and hypercellularity, glomerular basement membrane double contours, and endocapillary hypercellularity. Multivariable analysis showed negative associations between eGFR and crescents, interstitial inflammation, and interstitialfibrosis/tubular atrophy. Proteinuria positively associated with endocapillary hypercellularity and glomerular basement membrane double contours. Analysis of second native biopsies did not demonstrate associations between immunosuppression treatment and improvement in histology. Using a composite outcome, risk of progression to kidney failure associated with eGFR and proteinuria at the time of biopsy, cellular/fibrocellular crescents, segmental sclerosis, and interstitial fibrosis/tubular atrophy scores. Conclusions: Our detailed assessment of kidney biopsy data indicated that cellular/fibrocellular crescents and interstitial fibrosis/tubular atrophy scores were significant determinants of deterioration in kidney function.
- Published
- 2022
25. Anti-CD20 should be the first line treatment in high-risk membranous nephropathy
- Author
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Ladan Zand and Fernando C Fervenza
- Subjects
Transplantation ,Nephrology - Abstract
Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults and if untreated can progress to endstage kidney disease. Factors considered to place a patient at high or very high risk for progression include elevated serum creatinine at baseline, declining kidney function, persistent heavy proteinuria (>8 g/24 h), or persistent NS, presence of life-threatening complications related to NS (such as venous thromboembolic events), or very high anti-PLA2R antibody titers (>150 RU/ml). Patients who are at high or very high risk of progression should be treated with immunosuppression therapy to induce remission of proteinuria and to avoid progressive loss of kidney function. Traditional forms of immunosuppression for patients with MN have included the use of cyclic courses of corticosteroids with cyclophosphamide or calcineurin inhibitors. These forms of therapy are associated with significant toxicity, e.g. corticosteroids (infections, diabetes, weight gain), cyclophosphamide (infertility, severe leukopenia, malignancy), and calcineurin inhibitors (hypertension, nephrotoxicity). The introduction of anti-CD20+ B-cell therapies in the late 1990s has changed the landscape. In this article we will argue that anti-CD20+ B therapy should be the treatment of choice for patients at high/very high risk of progression when considering its efficacy and side-effect profile.
- Published
- 2023
26. Heterogeneity of Target Antigens in Sarcoidosis-Associated Membranous Nephropathy
- Author
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Dalia Zubidat, Benjamin Madden, Satoru Kudose, Samih H. Nasr, Luca Nardelli, Fernando C. Fervenza, and Sanjeev Sethi
- Subjects
Nephrology - Published
- 2023
27. Proprotein convertase subtilisin/kexin type 6 (PCSK6) is a likely antigenic target in membranous nephropathy and nonsteroidal anti-inflammatory drug use
- Author
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Sanjeev Sethi, Marta Casal Moura, Benjamin Madden, Hanna Debiec, Samih H. Nasr, Christopher P. Larsen, LouAnn Gross, Vivian Negron, Raman Deep Singh, Karl A. Nath, Aaron J. Storey, Ulrich Specks, Fernando C. Fervenza, Pierre Ronco, and Tiffany N. Caza
- Subjects
Nephrology - Published
- 2023
28. Hematopoietic Stem Cell Transplant-Membranous Nephropathy Is Associated with Protocadherin FAT1
- Author
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Sanjeev Sethi, Benjamin Madden, Marta Casal Moura, Samih H. Nasr, Nattawat Klomjit, LouAnn Gross, Vivian Negron, M. Cristine Charlesworth, Mariam P. Alexander, Nelson Leung, Ulrich Specks, Fernando C. Fervenza, and Mark Haas
- Subjects
Male ,Receptors, Phospholipase A2 ,Hematopoietic Stem Cell Transplantation ,High-Temperature Requirement A Serine Peptidase 1 ,General Medicine ,Cadherins ,Glomerulonephritis, Membranous ,Protocadherins ,Clinical Research ,Tandem Mass Spectrometry ,Nephrology ,Immunoglobulin G ,Humans ,Female ,Autoantibodies - Abstract
BACKGROUND: Membranous nephropathy (MN) is a common cause of proteinuria in patients receiving a hematopoietic stem cell transplant (HSCT). The target antigen in HSCT-associated MN is unknown. METHODS: We performed laser microdissection and tandem mass spectrometry (MS/MS) of glomeruli from 250 patients with PLA2R-negative MN to detect novel antigens in MN. This was followed by immunohistochemical (IHC)/immunofluorescence (IF) microscopy studies to localize the novel antigen. Western blot analyses using serum and IgG eluted from frozen biopsy specimen to detect binding of IgG to new 'antigen'. RESULTS: MS/MS detected a novel protein, protocadherin FAT1 (FAT1), in nine patients with PLA2R-negative MN. In all nine patients, MN developed after allogeneic HSCT (Mayo Clinic discovery cohort). Next, we performed MS/MS in five patients known to have allogeneic HSCT-associated MN (Cedar Sinai validation cohort). FAT1 was detected in all five patients by MS/MS. The total spectral counts for FAT1 ranged from 8 to 39 (mean±SD, 20.9±10.1). All 14 patients were negative for known antigens of MN, including PLA2R, THSD7A, NELL1, PCDH7, NCAM1, SEMA3B, and HTRA1. Kidney biopsy specimens showed IgG (2 to 3+) with mild C3 (0 to 1+) along the GBM; IgG4 was the dominant IgG subclass. IHC after protease digestion and confocal IF confirmed granular FAT1 deposits along the GBM. Lastly, Western blot analyses detected anti-FAT1 IgG and IgG4 in the eluate obtained from pooled frozen kidney biopsy tissue and in the serum of those with FAT1-asssociated MN, but not from those with PLA2R-associated MN. CONCLUSIONS: FAT1-associated MN appears to be a unique type of MN associated with HSCT. FAT1-associated MN represents a majority of MN associated with HSCT.
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- 2022
29. Acute glomerulonephritis
- Author
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Sanjeev, Sethi, An S, De Vriese, and Fernando C, Fervenza
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Male ,Proteinuria ,Glomerulonephritis ,Biopsy ,Humans ,Female ,Glomerulonephritis, IGA ,General Medicine ,Antibodies, Antineutrophil Cytoplasmic ,Hematuria - Abstract
Glomerulonephritis is a heterogeneous group of disorders that present with a combination of haematuria, proteinuria, hypertension, and reduction in kidney function to a variable degree. Acute presentation with full blown nephritic syndrome or rapidly progressive glomerulonephritis is uncommon and is mainly restricted to patients with post-infectious glomerulonephritis, anti-neutrophil cytoplasmic antibodies-associated vasculitis, and anti-glomerular basement membrane disease. Most frequently, patients present with asymptomatic haematuria and proteinuria with or without reduced kidney function. All glomerulonephritis disorders can show periods of exacerbation, but disease flairs characteristically occur in patients with IgA nephropathy or C3 glomerulopathy. The gold standard for the diagnosis of a glomerulonephritis is a kidney biopsy, with a hallmark glomerular inflammation that translates into various histopathological patterns depending on the location and severity of the glomerular injury. Traditionally, glomerulonephritis was classified on the basis of the different histopathological patterns of injury. In the last few years, substantial progress has been made in unravelling the underlying causes and pathogenetic mechanisms of glomerulonephritis and a causal approach to the classification of glomerulonephritis is now favoured over a pattern-based approach. As such, glomerulonephritis can be broadly classified as immune-complex glomerulonephritis (including infection-related glomerulonephritis, IgA nephropathy, lupus nephritis, and cryoglobulinaemic glomerulonephritis), anti-neutrophil cytoplasmic antibodies-associated (pauci-immune) glomerulonephritis, anti-glomerular basement membrane glomerulonephritis, C3 glomerulopathy, and monoclonal immunoglobulin-associated glomerulonephritis. We provide an overview of the clinical presentation, pathology, and the current therapeutic approach of the main representative disorders in the spectrum of glomerulonephritis.
- Published
- 2022
30. Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation
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Minnie M. Sarwal, Nicole Arceneaux, Jonathan Barratt, Mark D. Stegall, Christine B. Sethna, Debbie S. Gipson, Shadab Ali, Richard J.H. Smith, Matthew C. Pickering, Lindsey Fuller, Brad H. Rovin, Ashley Frazer-Abel, Carla M. Nester, Rasheed Gbadegesin, Fernando C. Fervenza, Gerald B. Appel, Samir V. Parikh, Daniel C. Cattran, Véronique Frémeaux-Bacchi, Cathie Spino, Sanjay Ram, Pierre Ronco, Laura Bailey-Wickins, Paolo Cravedi, Jonathan J. Hogan, Joshua M. Thurman, Laurence H. Beck, John D. Mahan, Marina Vivarelli, Isa Ashoor, Michelle N. Rheault, Elif Erkan, David L. Feldman, Richard J. Quigg, Richard A. Lafayette, Peter S. Heeger, Andrew S. Bomback, Moglie le Quintrec-Donnette, Michelle A. Hladunewich, Christoph Licht, Krzysztof Kiryluk, and Howard Trachtman
- Subjects
medicine.medical_specialty ,business.industry ,Clinical study design ,MEDLINE ,Foundation (evidence) ,Complement (complexity) ,Clinical trial ,Nephrology ,medicine ,Patient representatives ,Intensive care medicine ,Risk assessment ,business ,Therapeutic strategy - Abstract
Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents a myriad of questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anti-complement therapy trials either planned or underway, the National Kidney Foundation (NKF) facilitated an all-virtual format scientific workshop entitled, "Improving Clinical Trials for Anti-complement Therapies in Complement-mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anti-complement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, subject risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.
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- 2022
31. Thyroid Disease, Hypertension, and Pregnancy: The Need for Balance Illustrated in 2 Cases
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Círia Sousa, Vesna D Garovic, Marius Stan, Fernando C Fervenza, and Andrea Kattah
- Subjects
Internal Medicine - Abstract
Thyroid dysfunction in pregnancy has been associated with hypertensive disorders of pregnancy and poor maternal and fetal outcomes. In this article, we describe two cases of significant thyroid dysfunction leading to new diagnoses of chronic hypertension in pregnancy and review physiologic changes in the thyroid gland, placenta and maternal cardiovascular system during pregnancy.
- Published
- 2023
32. Future landscape for the management of membranous nephropathy
- Author
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Fernando Caravaca-Fontán, Federico Yandian, and Fernando C Fervenza
- Subjects
Transplantation ,Nephrology - Abstract
Among all glomerular diseases, membranous nephropathy (MN) is perhaps the one in which major progress has been made in recent decades, in both the understanding of the pathogenesis and treatment. Despite the overall significant response rates to these therapies—particularly rituximab and cyclical regimen based on corticosteroids and cyclophosphamide—cumulative experience over the years has shown, however, that 20%–30% of cases may confront resistant disease. Thus, these unmet challenges in the treatment of resistant forms of MN require newer approaches. Several emerging new agents—developed primarily for the treatment of hematological malignancies or rheumatoid diseases—are currently being evaluated in MN. Herein we conducted a narrative review on future therapeutic strategies in the disease. Among the different novel therapies, newer anti-CD20 agents (e.g. obinutuzumab), anti-CD38 (e.g. daratumumab, felzartamab), immunoadsorption or anti-complement therapies (e.g. iptacopan) have gained special attention. In addition, several technologies and innovations developed primarily for cancer (e.g. chimeric antigen receptor T-cell therapy, sweeping antibodies) seem particularly promising. In summary, the future therapeutic landscape in MN seems encouraging and will definitely move the management of this disease towards a more precision-based approach.
- Published
- 2023
33. Implementation of genomic medicine for rare disease in a tertiary healthcare system: Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD)
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Filippo Pinto e Vairo, Jennifer L. Kemppainen, Carolyn R. Rohrer Vitek, Denise A. Whalen, Kayla J. Kolbert, Kaitlin J. Sikkink, Sarah A. Kroc, Teresa Kruisselbrink, Gabrielle F. Shupe, Alyssa K. Knudson, Elizabeth M. Burke, Elle C. Loftus, Lorelei A. Bandel, Carri A. Prochnow, Lindsay A. Mulvihill, Brittany Thomas, Dale M. Gamble, Courtney B. Graddy, Giovanna G. Moreno Garzon, Idara U. Ekpoh, Eva M. Carmona Porquera, Fernando C. Fervenza, Marie C. Hogan, Mireille El Ters, Kenneth J. Warrington, III John M. Davis, Matthew J. Koster, Amir B. Orandi, Matthew L. Basiaga, Adrian Vella, Seema Kumar, Ana L. Creo, Aida N. Lteif, Siobhan T. Pittock, Peter J. Tebben, Ejigayehu G. Abate, Avni Y. Joshi, Elizabeth H. Ristagno, Mrinal S. Patnaik, Lisa A. Schimmenti, Radhika Dhamija, Sonia M. Sabrowsky, Klaas J. Wierenga, Mira T. Keddis, Niloy Jewel J. Samadder, Richard J. Presutti, Steven I. Robinson, Michael C. Stephens, Lewis R. Roberts, William A. Faubion, Sherilyn W. Driscoll, Lily C. Wong-Kisiel, Duygu Selcen, Eoin P. Flanagan, Vijay K. Ramanan, Lauren M. Jackson, Michelle L. Mauermann, Victor E. Ortega, Sarah A. Anderson, Stacy L. Aoudia, Eric W. Klee, Tammy M. McAllister, and Konstantinos N. Lazaridis
- Abstract
Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1,152 patients have been evaluated with an overall solve rate of 14.1% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.
- Published
- 2023
34. Proteomic profile of uninvolved versus crescentic glomeruli in MPO-ANCA-associated vasculitis
- Author
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Amit Sethi, Joseph Grande, Ulrich Specks, and Fernando C Fervenza
- Subjects
Transplantation ,Nephrology - Published
- 2023
35. Proteomic Analysis of Complement Proteins in Glomerular Diseases
- Author
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Sanjeev Sethi, Lilian Monteiro P. Palma, Jason D. Theis, and Fernando C. Fervenza
- Subjects
Nephrology ,Clinical Research - Abstract
INTRODUCTION: Complement plays an important role in the pathogenesis of glomerulonephritis (GN). Even though the underlying etiology of GN might be different, complement activation with subsequent glomerular deposition of complement proteins result in glomerular injury and progression of the lesions. Routine immunofluorescence microscopy (IF) includes staining for only complement factors C3c and C1q. Therefore, with regard to evaluation of the complement pathways, routine kidney biopsy provides only limited information. METHODS: In this study, using laser microdissection of glomeruli followed by mass spectrometry, complement proteins and pathways involved in GN were analyzed. RESULTS: We found that C3 followed by C9 are the most abundant complement proteins in GN, indicating activation of classical or lectin or alternative, and terminal pathways, either exclusively or in a combination of pathways. Furthermore, depending on the type of GN, C4A and/or C4B were also present. Therefore, membranous nephropathy (MN), fibrillary GN, and infection-related GN showed C4A dominant pathways, whereas lupus nephritis (LN), proliferative GN with monoclonal Ig deposits, monoclonal Ig deposition disease (MIDD), and immunotactoid glomerulopathy showed C4B dominant pathways. Significant deposition of complement regulatory proteins, factor H-related protein-1 (FHR-1) and factor H-related protein-5 (FHR-5), were also detected in most GN. CONCLUSIONS: This study shows accumulation of specific complement proteins in GN. The complement pathways, complement proteins, and the amount of complement protein deposition are variable in different types of GN. Selective targeting of complement pathways may be a novel option in the treatment of GN.
- Published
- 2023
36. Dendrin in IgA nephropathy: protective or marker of early disease?
- Author
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Rosanna Coppo and Fernando C Fervenza
- Subjects
Transplantation ,Nephrology - Published
- 2022
37. Acute Treatment Effects on GFR in Randomized Clinical Trials of Kidney Disease Progression
- Author
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Jack F.M. Wetzels, Marian Goicoechea, Mark Woodward, Jürgen Floege, Ronald D. Perrone, Hiddo Heerspink, Francesco Locatelli, Brendon L. Neuen, Di Xie, Philip Kam-Tao Li, Tom Greene, Bart Maes, Annalisa Perna, Christoph Wanner, Tazeen H. Jafar, Enyu Imai, Edward F. Vonesh, Shiyuan Miao, Juhi Chaudhari, Julia B. Lewis, Lesley A. Inker, Hocine Tighiouart, William G. Herrington, Francesco Paolo Schena, Manuel Praga, Fernando C. Fervenza, Tak Mao Chan, Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), and Groningen Kidney Center (GKC)
- Subjects
Acute effects ,Male ,medicine.medical_specialty ,Randomization ,030232 urology & nephrology ,Renal function ,Disease ,030204 cardiovascular system & hematology ,urologic and male genital diseases ,law.invention ,Renin-Angiotensin System ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Internal medicine ,Intervention Type ,Medicine ,Albuminuria ,Humans ,Renal Insufficiency, Chronic ,Sodium-Glucose Transporter 2 Inhibitors ,Antihypertensive Agents ,Randomized Controlled Trials as Topic ,business.industry ,General Medicine ,medicine.disease ,female genital diseases and pregnancy complications ,3. Good health ,Nephrology ,Creatinine ,Disease Progression ,Female ,medicine.symptom ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,Immunosuppressive Agents ,Kidney disease ,Meta-Analysis ,Glomerular Filtration Rate - Abstract
Background: Acute changes in glomerular filtration rate (GFR) can occur following initiation of interventions for chronic kidney disease (CKD) progression. These complicate the interpretation of treatment effects on long term progression of (CKD). We sought to assess the magnitude and consistency of acute effects in randomized clinical trials (RCT) and explore factors that might impact them. Methods: We performed a meta-analysis of 53 RCTs for CKD progression enrolling 56,413 participants that had at least one estimated GFR measurement by six months following randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable meta-regression to assess the impact of intervention type, disease state, baseline GFR and albuminuria on the magnitude of acute effects. Results: The mean acute effect across all studies was -0.21 mL/min/1.73m2 (95% CI -0.63 to 0.22) over three months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 mL/min/1.73m2). Negative average acute effects were observed in renin angiotensin system blockade, blood pressure lowering and sodium-glucose cotransporter 2 inhibitor trials while positive acute effects were observed in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with higher mean baseline GFR. Conclusion: The magnitude and consistency of acute GFR effects varies across different interventions, and is larger at higher baseline GFR. Understanding the nature and magnitude of the acute effects can help inform the optimal design of RCTs in CKD evaluating kidney disease progression.
- Published
- 2022
38. COVID-19 Vaccination and Glomerulonephritis
- Author
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Ladan Zand, Arvind Garg, Marie C. Hogan, Fernando C. Fervenza, Samih H. Nasr, Ziad Zoghby, Marwan Abu Minshar, Mariam P. Alexander, and Nattawat Klomjit
- Subjects
medicine.medical_specialty ,COVID-19 Vaccines ,BNT162b ,Gastroenterology ,Nephropathy ,Focal segmental glomerulosclerosis ,Membranous nephropathy ,Clinical Research ,Internal medicine ,medicine ,Humans ,Minimal change disease ,Hematuria ,focal segmental glomerulosclerosis ,Autoimmune disease ,SARS-CoV-2 ,business.industry ,Vaccination ,COVID-19 ,membranous nephropathy ,AstraZeneca ,Glomerulonephritis, IGA ,Glomerulonephritis ,IgA nephropathy ,mRNA1273 ,medicine.disease ,FSGS ,mRNA vaccine ,minimal change disease ,Nephrology ,atypical anti-GBM ,business ,Vaccine ,Nephritis ,Sinovac ,glomerulonephritis - Abstract
Background MRNA COVID-19 vaccine is more effective than traditional vaccines due to superior immune activation. However, the impact of mRNA COVID-19 vaccine on triggering de novo/relapsing glomerulonephritis (GN) is limited. We report a case series of patients who developed new or relapsing GN post vaccination. Method We evaluated baseline characteristics, vaccine type and clinical outcomes of 13 patients from our institution who had a new diagnosis or relapse of their GN post mRNA COVID-19 vaccination. Results Of 13 patients, 8 patients were newly diagnosed GNs and 5 patients had relapse. Median age was 62 years (range 19-83 years). Autoimmune disease (38%) was the most prevalent underlying disease followed by cancer (23%). Majority of patients were white male. IgA nephropathy (IgAN) was the most common GN in our series (5 patients, 38%) followed by membranous nephropathy (MN) (3 patients, 23%). One patient with IgAN had evidence of IgA deposits prior to vaccination suggesting that the immune activation following vaccination triggered a flare of the disease. Our case series also included the first case report of tip-variant focal segmental glomerulosclerosis, NELL-1 associated MN, and atypical anti-GBM nephritis. Seventy seven percent developed acute kidney injury with the majority being KDIGO stage 1 (67%). Outcome are favorable with 80% responding to therapy. Conclusions New cases and relapse of GN can present shortly after mRNA COVID-19 vaccination. New cases of IgAN may result from unmasking of undiagnosed IgAN due to robust immune activation rather than development of new deposits.
- Published
- 2021
39. Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases
- Author
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Frank Bridoux, David Jayne, Yusuke Suzuki, Amy Earley, Kelly A. Burdge, Marina Vivarelli, Zhihong Liu, Jai Radhakrishnan, Adrian Liew, Keisha L. Gibson, Marcello Tonelli, Richard J. Glassock, Sydney C.W. Tang, Sharon G. Adler, Jan-Stephan F. Sanders, H. Terence Cook, Jonathan C. Craig, Vladimir Tesar, Sanjeev Sethi, Jonathan Barratt, Pierre Ronco, Elizabeth M. Rave, Michael Cheung, Brad H. Rovin, David J. Tunnicliffe, Carla M. Nester, Juan M. Mejia-Vilet, Vivekanand Jha, Martin Howell, Fernando C. Fervenza, Tak Mao Chan, Lyubov Lytvyn, Jürgen Floege, Jack F.M. Wetzels, Heather N. Reich, Groningen Kidney Center (GKC), Groningen Institute for Organ Transplantation (GIOT), Jayne, David [0000-0002-1712-0637], and Apollo - University of Cambridge Repository
- Subjects
Adult ,medicine.medical_specialty ,Evidence-based practice ,Kidney ,Glomerulonephritis, Membranous ,anti-GBM ,Nephropathy ,IgA vasculitis ,Glomerulonephritis ,Focal segmental glomerulosclerosis ,systematic review ,Membranous nephropathy ,evidence-based ,medicine ,Humans ,complement ,Minimal change disease ,C3 ,Child ,Intensive care medicine ,glomerular diseases ,infection-related glomerulonephritis ,KDIGO ,lupus nephritis ,ANCA ,nephrotic syndrome ,business.industry ,MPGN ,Nephrosis, Lipoid ,membranous nephropathy ,AAV ,Glomerulonephritis, IGA ,IgA nephropathy ,Guideline ,medicine.disease ,FSGS ,minimal change disease ,Systematic review ,Nephrology ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,guideline - Abstract
Kidney international 100(4), 753-779 (2021). doi:10.1016/j.kint.2021.05.015, Published by Elsevier, New York, NY
- Published
- 2021
40. Incorporation of Genetic Studies in the Kidney Transplant Evaluation Clinic: The Value of a Multidisciplinary Approach
- Author
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Mireille El Ters, Filippo Pinto e Vairo, Carri Prochnow, Carrie Schinstock, Patrick Dean, Jennifer Kemppainen, Konstantinos Lazaridis, Fernando Cosio, Fernando C. Fervenza, Lynn Cornell, Hatem Amer, and Marie C. Hogan
- Subjects
Transplantation - Abstract
Recent studies identified underlying genetic causes in a proportion of patients with various forms of kidney disease. In particular, genetic testing reclassified some focal segmental glomerulosclerosis (FSGS) cases into collagen type 4 (COL4)-related nephropathy. This knowledge has major implications for counseling prospective transplant recipients about recurrence risk and screening biologically related donors. We describe our experience incorporating genetic testing in our kidney transplant multidisciplinary practice.Patients' DNA was analyzed using whole exome sequencing for a comprehensive kidney gene panel encompassing 344 genes associated with kidney diseases and candidate genes highly expressed in the kidney. Results were correlated with phenotype by a multidisciplinary committee of nephrologists, renal pathologists, geneticists, and genetic counselors. Between October 2018 and July 2020, 30 recipient and 5 donor candidates completed testing.Among recipient candidates, 24 (80%) carried the diagnosis of FSGS, 2 (6.7%) tubulointerstitial nephritis, and 1 (3.3%) nephrolithiasis, and 3 (10%) had an unknown cause of kidney disease. The yield for pathogenic/likely pathogenic variants was 43.3%, with majority being COL4 variants (53.8%). Among those with FSGS diagnosis, the yield was 10 of 24 (41.6%), with 29% reclassified into a COL4-related nephropathy. Family history of kidney disease was the only clinical characteristic difference between recipients with positive and negative results (76.9 versus 29.4%; P = 0.025). One of 5 donors tested positive for a pathogenic/likely pathogenic variant and was excluded from donation.We conclude that thoughtful use of genetic testing can be valuable for kidney donor selection and transplant recipient management.
- Published
- 2022
41. 1H Nuclear Magnetic Resonance Spectroscopy-Based Methods for the Quantification of Proteins in Urine
- Author
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Slobodan Macura, Ivan Vuckovic, Shane A. Bobart, John C. Lieske, M. Cristine Charlesworth, Milovan Šuvakov, Fernando C. Fervenza, and Aleksandar Denic
- Subjects
chemistry.chemical_compound ,Laser linewidth ,Trimethylsilyl ,chemistry ,Analytical chemistry ,Bicinchoninic acid assay ,Nuclear magnetic resonance spectroscopy ,Spectroscopy ,Two-dimensional nuclear magnetic resonance spectroscopy ,Small molecule ,Spectral line ,Analytical Chemistry - Abstract
We described several postprocessing methods to measure protein concentrations in human urine from existing 1H nuclear magnetic resonance (NMR) metabolomic spectra: (1) direct spectral integration, (2) integration of NCD spectra (NCD = 1D NOESY-CPMG), (3) integration of SMolESY-filtered 1D NOESY spectra (SMolESY = Small Molecule Enhancement SpectroscopY), (4) matching protein patterns, and (5) TSP line integral and TSP linewidth. Postprocessing consists of (a) removal of the metabolite signals (demetabolization) and (b) extraction of the protein integral from the demetabolized spectra. For demetabolization, we tested subtraction of the spin-echo 1D spectrum (CPMG) from the regular 1D spectrum and low-pass filtering of 1D NOESY by its derivatives (c-SMolESY). Because of imperfections in the demetabolization, in addition to direct integration, we extracted protein integrals by the piecewise comparison of demetabolized spectra with the reference spectrum of albumin. We analyzed 42 urine samples with protein content known from the bicinchoninic acid (BCA) assay. We found excellent correlation between the BCA assay and the demetabolized NMR integrals. We have provided conversion factors for calculating protein concentrations in mg/mL from spectral integrals in mM. Additionally, we found the trimethylsilyl propionate (TSP, NMR standard) spectral linewidth and the TSP integral to be good indicators of protein concentration. The described methods increase the information content of urine NMR metabolomics spectra by informing clinical studies of protein concentration.
- Published
- 2021
42. Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection
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Stephen B. Erickson, Andrew Bentall, Mireille El Ters, Pavel N. Pichurin, Fernando C. Fervenza, Marie C. Hogan, Loren P. Herrera Hernandez, Ladan Zand, Jing Miao, Aleksandra Kukla, Eddie L. Greene, Konstantinos N. Lazaridis, Carri A. Prochnow, Sanjeev Sethi, Filippo Vairo, and Emily C. Lisi
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medicine.medical_specialty ,Univariate analysis ,medicine.diagnostic_test ,urogenital system ,business.industry ,General Medicine ,Odds ratio ,urologic and male genital diseases ,medicine.disease ,female genital diseases and pregnancy complications ,Focal segmental glomerulosclerosis ,Internal medicine ,Biopsy ,medicine ,Family history ,business ,Nephrotic syndrome ,Kidney disease ,Genetic testing - Abstract
Objective To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. Patients and Methods Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. Results The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P Conclusion In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.
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- 2021
43. Kidney biopsy chronicity grading in antineutrophil cytoplasmic antibody-associated vasculitis
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Marta Casal Moura, Sanjeev Sethi, Ulrich Specks, and Fernando C. Fervenza
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medicine.medical_specialty ,Biopsy ,Renal function ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,Kidney ,Gastroenterology ,Antibodies, Antineutrophil Cytoplasmic ,Glomerulonephritis ,Internal medicine ,medicine ,Humans ,Peroxidase ,Retrospective Studies ,Anti-neutrophil cytoplasmic antibody ,Transplantation ,medicine.diagnostic_test ,business.industry ,Glomerulosclerosis ,Retrospective cohort study ,medicine.disease ,medicine.anatomical_structure ,Nephrology ,Kidney Diseases ,Vasculitis ,business - Abstract
Background Kidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined. Methods We conducted a retrospective cohort study of myeloperoxidase (MPO)- or proteinase 3 (PR3)-ANCA-positive patients with AAV and active renal disease. We applied the Mayo Clinic Chronicity Score (MCCS) and validated and evaluated its implications on outcome prediction in AAV-GN. Results We analyzed 329 patients with kidney biopsies available to score. The extent of chronicity was graded by MCCS as minimal [102 (31.0%)], mild [106 (32.2%)], moderate [86 (26.1%)] and severe [35 (10.6%)]. The MCCS grades correlated with the degree of renal function impairment at presentation [mean estimated glomerular filtration rate (eGFR) 48.3 versus 29.2 versus 23.7 versus 18.5 mL/min/1.73 m2, respectively; P < 0.0001]. Higher degrees of the individual components of the MCCS (glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriosclerosis) were associated with lower median eGFR (P < 0.0001) and decreased event-free [kidney failure (KF) and death] survival (P = 0.002, P < 0.0001, P < 0.0001 and P = 0.017, respectively). Patients with lower MCCS grades recovered renal function more frequently (P < 0.0001). Increasing MCCS grades were associated with decreased renal recovery (P = 0.001), more frequent events and shorter time to KF (P < 0.0001), KF and death (P < 0.0001) and death (P = 0.042), independent of the remission induction treatment used (cyclophosphamide or rituximab). The MCCS stratified renal outcomes for each MCCS grade and can be used in clinical practice as a cutoff for KF prediction (MCCS ≥4). Conclusions Chronic changes on kidney histology independently predict renal function, outcomes and response to treatment in AAV-GN.
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- 2021
44. Incidence, Prevalence, and Mortality of Lupus Nephritis: A Population-Based Study Over Four Decades-The Lupus Midwest Network (LUMEN)
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Mehmet, Hocaoglu, Maria O, Valenzuela-Almada, Jesse Y, Dabit, Shirley-Ann, Osei-Onomah, Baptiste, Chevet, Rachel E, Giblon, Ladan, Zand, Fernando C, Fervenza, Charles G, Helmick, Cynthia S, Crowson, and Alí, Duarte-García
- Abstract
There is paucity of population-based studies investigating the epidemiology of lupus nephritis (LN) in the US and long-term secular trends of the disease and its outcomes. We aimed to examine the epidemiology of LN in a well-defined eight-county region in the US.Patients with incident LN between 1976 and 2018 (1976-2009 Olmsted County, 2010-2018 eight-county region) in Minnesota were identified. Age- and sex-specific incidence rates and point prevalence for four decades, adjusted to the projected 2000 US population, were reported. Standardized mortality ratios (SMR), survival rates, and time to end-stage renal disease (ESRD) were estimated.There were 72 patients with incident LN between 1976-2018. Mean age at diagnosis was 38.4 years (SD 16.24), 76% were female, and 69% non-Hispanic White. Average annual LN incidence between 1976 and 2018 was 1 per 100,000 population (95%CI 0.8-1.3) and highest in the 30-39 age group. Between 1976-1989 and 2000-2018 periods, overall incidence of LN increased from 0.7 to 1.3 per 100,000, but this was not statistically significant. Estimated LN prevalence increased from 16.8 in 1985 to 21.2 per 100,000 in 2015. LN had an SMR of 6.33 (95% CI 3.81-9.89) with no improvement in mortality gap in the last four decades. At 10 years, survival was 70%, and 13% had ESRD.The incidence and prevalence of LN in this area increased in the last four decades. LN patients have poor outcomes with high rates of ESRD and mortality rates six times that of the general population. This article is protected by copyright. All rights reserved.
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- 2022
45. Autoreactive plasmablasts after B cell depletion with rituximab and relapses in ANCA-associated vasculitis
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Alvise, Berti, Sophie, Hillion, Maximilian F, Konig, Marta, Casal Moura, Amber M, Hummel, Eva, Carmona, Tobias, Peikert, Fernando C, Fervenza, Cees G M, Kallenberg, Carol A, Langford, Peter A, Merkel, Paul A, Monach, Philip, Seo, Robert F, Spiera, Paul, Brunetta, E William, St Clair, Kristina M, Harris, John H, Stone, Guido, Grandi, Jacques-Olivier, Pers, Ulrich, Specks, and Divi, Cornec
- Abstract
Autoreactive B cells are responsible for ANCA production in ANCA-associated vasculitis (AAV). Rituximab depletes circulating B cells including autoreactive ones. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV.Sequential flow-cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 proteinase-3 (PR3)-ANCAAt B cell recurrence, PR3The composition of autoreactive B cell pool varies significantly following rituximab treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses.
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- 2022
46. Safety and Efficacy of Daratumumab in Patients with Proliferative GN with Monoclonal Immunoglobulin Deposits
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Mireille El Ters, Nelson Leung, S. Vincent Rajkumar, Ladan Zand, Sanjeev Sethi, and Fernando C. Fervenza
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Glomerulonephritis, Membranoproliferative ,Anemia ,Paraproteinemias ,Renal function ,Antineoplastic Agents ,Pilot Projects ,030204 cardiovascular system & hematology ,Gastroenterology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Multiple myeloma ,Aged ,Aged, 80 and over ,Leukopenia ,Proteinuria ,business.industry ,Antibodies, Monoclonal ,Daratumumab ,General Medicine ,Middle Aged ,medicine.disease ,Treatment Outcome ,Nephrology ,Immunoglobulin G ,Monoclonal ,Female ,medicine.symptom ,business - Abstract
Background Treatment of proliferative GN with monoclonal Ig deposits (PGNMID) is not established. A monoclonal anti-CD38 antibody (daratumumab) is effective in treating multiple myeloma. Abnormal plasma cell clones may play a role in the pathogenesis of PGNMID. Methods We evaluated daratumumab's safety and efficacy in an open-label, phase 2 trial in 11 adults with PGNMID and one with C3 glomerulopathy (C3G) with monoclonal gammopathy. Patients had an eGFR >20 ml/min per 1.73 m2 and proteinuria >1 g/d. They received daratumumab intravenously (16 mg/kg) once weekly for 8 weeks, and then every other week for eight additional doses. Primary outcome was safety, defined as major infections, grade 3 or 4 anemia, leukopenia, or thrombocytopenia. Secondary outcomes were rate of complete remission (proteinuria 50% reduction in 24-hour proteinuria with Results One patient with C3G had GN unrelated to the monoclonal gammopathy, and one with PGNMID did not complete the first infusion. Five serious adverse events occurred. During the 12 months of the trial, six of the ten patients with PGNMID who received at least one dose of daratumumab had a partial response, and four had a complete response (an overall response rate of 100%). Three patients experienced relapse, two of whom re-entered partial remission after resuming daratumumab therapy. Proteinuria declined significantly, from a median of 4346 mg/d to 1264 mg/d by 12 months. Conclusions Daratumumab demonstrated an acceptable safety profile and resulted in significant improvement in proteinuria while stabilizing kidney function in patients with PGNMID, suggesting the drug merits further investigation. Clinical trial registry name and registration number Daratumumab in Treatment of PGNMID and C3 GN, NCT03095118.
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- 2021
47. Immune-Complex Glomerulonephritis After COVID-19 Infection
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Sanjeev Sethi, Sandra M Hermann, Mathew R D'Costa, Fernando C. Fervenza, and Samih H. Nasr
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Coronavirus disease 2019 (COVID-19) ,Nephrology ,business.industry ,Immunology ,MEDLINE ,Medicine ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,business ,Immune complex glomerulonephritis - Published
- 2021
48. MAC Plus Study: A Retrospective Study Correlating DNA Variants, Clinical Course and Outcomes from 187 Patients Who Underwent Testing Using an Atypical Hemolytic Uremic Syndrome and Thrombotic Microangiopathy Genetic Sequencing Panel
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Jihyun Moon, Jamey Kain, Fernando C. Fervenza, Stephen B Erickson, Prince Singh, Shahrzad Tehranian, Craig B. Langman, Ramy Hanna, Paul Brakeman, Christopher C. Dvorak, Shaun David Lawicki, Amita Sharma, Jooeun Lim, Sujatha Venkataramani, Mike Ero, and Bradley Lewis
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
49. Prognostic Value of Diffuse Crescentic Lesions in Fibrillary Glomerulonephritis
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Vincent Javaugue, Samar M. Said, Lihong Bu, Frank Bridoux, Arnaud François, Jean-Michel Goujon, Ramy Fayad, Dennis Ross, Ashok Sastry, Fernando C. Fervenza, Nelson Leung, and Samih H. Nasr
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Nephrology - Published
- 2022
50. A Target Antigen–Based Approach to the Classification of Membranous Nephropathy
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Casal Moura Marta, Sanjeev Sethi, Julie A. Vrana, Samar M. Said, John C. Lieske, Shane A. Bobart, An S. De Vriese, Samih H. Nasr, Mariam P. Alexander, Callen D. Giesen, Fernando C. Fervenza, and Shahrzad Tehranian
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Anti-nuclear antibody ,Disease ,N-Acetylglucosaminyltransferases ,Malignancy ,Glomerulonephritis, Membranous ,Severity of Illness Index ,Antigen ,Membranous nephropathy ,Humans ,Medicine ,Antigens ,Neural Cell Adhesion Molecules ,Pathological ,Aged ,Autoantibodies ,business.industry ,Receptors, Phospholipase A2 ,Retrospective cohort study ,General Medicine ,Middle Aged ,Cadherins ,medicine.disease ,Immunohistochemistry ,Protocadherins ,Cohort ,Female ,Thrombospondins ,business - Abstract
Objective To describe the clinical and pathological phenotype of membranous nephropathy (MN) associated with M-type-phospholipase–A2-receptor (PLA2R), thrombospondin-type-1-domain-containing-7A (THSD7A), semaphorin 3B (SEMA3B), neural-epidermal-growth-factor-like-1-protein (NELL-1), protocadherin 7 (PCDH7), exostosin 1/exostosin 2 (EXT1/EXT2) and neural cell adhesion molecule 1 (NCAM-1) as target antigens. Methods A retrospective cohort of 270 adult patients with biopsy-proven MN diagnosed between January 2015 and April 2020 was classified as PLA2R-, THSD7A-, SEMA3B-, NELL-1–, PCDH7-, EXT1/EXT2-, NCAM-1–associated or septuple-negative MN using serologic tests, immunostaining, and/or mass spectrometry. Clinical, biochemical, pathologic, and follow-up data were systematically abstracted from the medical records, including disease activity of conditions traditionally associated with MN and occurring within 5 years of MN diagnosis. Results Patients with PLA2R-associated MN were predominantly middle-aged white men without associated disease. The presence of associated disease did not affect the clinical and pathologic characteristics of PLA2R-associated MN, suggesting that they were coincidental rather than causally linked. THSD7A-, NELL-1–, PCDH7-, and NCAM-1–associated MN were rare and SEMA3B-associated MN was not discovered in our cohort. EXT1/EXT2-associated MN was primarily diagnosed in younger women with active systemic autoimmunity. A significant proportion of septuple-negative patients had associated malignancy or systemic autoimmunity. Conclusion The widely used distinction between primary and secondary MN has limitations. We propose a refined terminology that combines the target antigen and associated disease to better classify MN and guide clinical decision making.
- Published
- 2021
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