Publications by authors named "Ettore Sabadini"

11 Publications

  • Page 1 of 1

Mycophenolate mofetil versus azathioprine in kidney transplant recipients on steroid-free, low-dose cyclosporine immunosuppression (ATHENA): A pragmatic randomized trial.

PLoS Med 2021 Jun 24;18(6):e1003668. Epub 2021 Jun 24.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy.

Background: We compared protection of mycophenolate mofetil (MMF) and azathioprine (AZA) against acute cellular rejection (ACR) and chronic allograft nephropathy (CAN) in kidney transplant recipients on steroid-free, low-dose cyclosporine (CsA) microemulsion maintenance immunosuppression.

Methods And Findings: ATHENA, a pragmatic, prospective, multicenter trial conducted by 6 Italian transplant centers, compared the outcomes of 233 consenting recipients of a first deceased donor kidney transplant induced with low-dose thymoglobulin and basiliximab and randomized to MMF (750 mg twice/day, n = 119) or AZA (75 to 125 mg/day, n = 114) added-on maintenance low-dose CsA microemulsion and 1-week steroid. In patients without acute clinical or subclinical rejections, CsA dose was progressively halved. Primary endpoint was biopsy-proven CAN. Analysis was by intention to treat. Participants were included between June 2007 and July 2012 and followed up to August 2016. Between-group donor and recipient characteristics, donor/recipient mismatches, and follow-up CsA blood levels were similar. During a median (interquartile range (IQR)) follow-up of 47.7 (44.2 to 48.9) months, 29 of 87 biopsied patients on MMF (33.3%) versus 31 of 88 on AZA (35.2%) developed CAN (hazard ratio (HR) [95% confidence interval (CI)]: 1.147 (0.691 to 1.904, p = 0.595). Twenty and 21 patients on MMF versus 34 and 14 on AZA had clinical [HR (95% CI): 0.58 (0.34 to 1.02); p = 0.057) or biopsy-proven subclinical [HR (95% CI): 1.49 (0.76 to 2.92); p = 0.249] ACR, respectively. Combined events [HR (95% CI): 0.85 (0.56 to 1.29); p = 0.438], patient and graft survival, delayed graft function (DGF), 3-year glomerular filtration rate (GFR) [53.8 (40.6;65.7) versus 49.8 (36.8;62.5) mL/min/1.73 m2, p = 0.50], and adverse events (AEs) were not significantly different between groups. Chronicity scores other than CAN predict long-term graft outcome. Study limitations include small sample size and unblinded design.

Conclusions: In this study, we found that in deceased donor kidney transplant recipients on low-dose CsA and no steroids, MMF had no significant benefits over AZA. This finding suggests that AZA, due to its lower costs, could safely replace MMF in combination with minimized immunosuppression.

Trial Registration: ClinicalTrials.gov NCT00494741; EUDRACT 2006-005604-14.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pmed.1003668DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8224852PMC
June 2021

C3 glomerulopathy in cystic fibrosis: a case report.

BMC Nephrol 2018 03 28;19(1):73. Epub 2018 Mar 28.

Unit of Pediatric Gastroenterology and Cystic Fibrosis, University of Messina, Messina, Italy.

Background: C3 glomerulonephritis is a rare glomerulopathy characterized at renal biopsy by C3 deposition, alone or with scanty immunoglobulins, as well as by an electron-dense material in mesangium, subendothelial and subepithelial space. An abnormal systemic activation of the alternative pathway of the complement cascade is responsible for the development of the disease if triggered by several possible environmental conditions. We report the first case in literature of a patient affected by cystic fibrosis and C3GN.

Case Presentation: Our case involves a young woman with cystic fibrosis, who had persistent microscopic hematuria, proteinuria and hypocomplementemia C3 for over three months. Renal biopsy confirmed the diagnosis of C3 glomerulopathy. Complement system dysregulation was tested and resulted in a strong terminal pathway activation proved by high levels of sC5b-9 complex, amounting to 1588 ng/ml (normal value < 400 ng/ml). Next generation sequencing (NGS) showed polymorphism in CFH (p.V62I in SCR1) and THBD (p.A473V), already known as pathogenic for C3GN, as well as a mutation in C3 (p.R102G) associated only with age-related macular degeneration (AMD) so far. Treatment was based on ACE inhibitors and kidney function is currently stable (GFR 50 ml/min, serum creatinine 1.7).

Conclusions: The co-existence of C3 glomerulopathy in a patient with CF, which is characterized by chronic infection/inflammation, makes this case an interesting model of chronic altered systemic activation of the alternative pathway of the complement cascade.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12882-018-0880-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5875003PMC
March 2018

Cluster Analysis Identifies Distinct Pathogenetic Patterns in C3 Glomerulopathies/Immune Complex-Mediated Membranoproliferative GN.

J Am Soc Nephrol 2018 01 13;29(1):283-294. Epub 2017 Oct 13.

IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica Bergamo, Italy.

Membranoproliferative GN (MPGN) was recently reclassified as alternative pathway complement-mediated C3 glomerulopathy (C3G) and immune complex-mediated membranoproliferative GN (IC-MPGN). However, genetic and acquired alternative pathway abnormalities are also observed in IC-MPGN. Here, we explored the presence of distinct disease entities characterized by specific pathophysiologic mechanisms. We performed unsupervised hierarchical clustering, a data-driven statistical approach, on histologic, genetic, and clinical data and data regarding serum/plasma complement parameters from 173 patients with C3G/IC-MPGN. This approach divided patients into four clusters, indicating the existence of four different pathogenetic patterns. Specifically, this analysis separated patients with fluid-phase complement activation (clusters 1-3) who had low serum C3 levels and a high prevalence of genetic and acquired alternative pathway abnormalities from patients with solid-phase complement activation (cluster 4) who had normal or mildly altered serum C3, late disease onset, and poor renal survival. In patients with fluid-phase complement activation, those in clusters 1 and 2 had massive activation of the alternative pathway, including activation of the terminal pathway, and the highest prevalence of subendothelial deposits, but those in cluster 2 had additional activation of the classic pathway and the highest prevalence of nephrotic syndrome at disease onset. Patients in cluster 3 had prevalent activation of C3 convertase and highly electron-dense intramembranous deposits. In addition, we provide a simple algorithm to assign patients with C3G/IC-MPGN to specific clusters. These distinct clusters may facilitate clarification of disease etiology, improve risk assessment for ESRD, and pave the way for personalized treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2017030258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5748907PMC
January 2018

Acute Kidney Injury and Hemolytic Anemia Secondary to Mycoplasma pneumoniae Infection.

Nephron 2017 7;137(2):148-154. Epub 2017 Jul 7.

IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.

Glomerulonephritis as well as kidney injury secondary to fulminant intravascular hemolysis are rare extrapulmonary manifestations of Mycoplasma pneumoniae infection. We describe a 50-year-old female diagnosed with M. pneumoniae infection-associated hemolytic anemia, characterized by negative cold agglutinin tests but with laboratory evidence of complement alternative pathway activation. The patient presented both with anemia and severe kidney failure and she was treated with steroids and red blood cell transfusions along with plasmapheresis. She also received a short course of antibiotics. Renal biopsy showed combined features of resolving postinfectious glomerulonephritis and hemolysis-associated extensive acute tubular injury characterized by renal hemosiderosis and intratubular hemoglobin casts. Electron microscopy revealed features of glomerular microangiopathic injury. The treatment led to complete disease remission and a favorable renal outcome at the first year follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000478991DOI Listing
June 2018

Mitochondrial-dependent Autoimmunity in Membranous Nephropathy of IgG4-related Disease.

EBioMedicine 2015 May 6;2(5):456-66. Epub 2015 Mar 6.

IRCCS - Istituto di Ricerche Farmacologiche "Mario Negri", Centro Anna Maria Astori, Science and Technology Park Kilometro Rosso, Bergamo, Italy.

The pathophysiology of glomerular lesions of membranous nephropathy (MN), including seldom-reported IgG4-related disease, is still elusive. Unlike in idiopathic MN where IgG4 prevails, in this patient IgG3 was predominant in glomerular deposits in the absence of circulating anti-phospholipase A2 receptor antibodies, suggesting a distinct pathologic process. Here we documented that IgG4 retrieved from the serum of our propositus reacted against carbonic anhydrase II (CAII) at the podocyte surface. In patient's biopsy, glomerular CAII staining increased and co-localized with subepithelial IgG4 deposits along the capillary walls. Patient's IgG4 caused a drop in cell pH followed by mitochondrial dysfunction, excessive ROS production and cytoskeletal reorganization in cultured podocytes. These events promoted mitochondrial superoxide-dismutase-2 (SOD2) externalization on the plasma membrane, becoming recognizable by complement-binding IgG3 anti-SOD2. Among patients with IgG4-related disease only sera of those with IgG4 anti-CAII antibodies caused low intracellular pH and mitochondrial alterations underlying SOD2 externalization. Circulating IgG4 anti-CAII can cause podocyte injury through processes of intracellular acidification, mitochondrial oxidative stress and neoantigen induction in patients with IgG4 related disease. The onset of MN in a subset of patients could be due to IgG4 antibodies recognizing CAII with consequent exposure of mitochondrial neoantigen in the context of multifactorial pathogenesis of disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2015.03.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485911PMC
May 2015

Membranous nephropathy associated with IgG4-related disease.

Am J Kidney Dis 2011 Aug 12;58(2):272-5. Epub 2011 Jun 12.

Mario Negri Institute for Pharmacological Research, Clinical Research Center for Rare Diseases Aldo e Cele Daccò, Ranica, Italy.

Immunoglobulin G4 (IgG4)-related systemic disease is a rare condition characterized by high levels of circulating IgG4 and IgG4-positive plasma cell infiltrates in various organs, including the pancreas, salivary glands, biliary tract, liver, lung, and kidney. We describe a case of a 54-year-old man with IgG4-related systemic disease presenting with autoimmune pancreatitis and Mikulicz disease. Steroid therapy decreased circulating IgG4 levels and promoted regression of clinical signs. Thereafter, an increase in serum IgG4 values was followed by the occurrence of nephrotic-range proteinuria. Kidney biopsy showed membranous nephropathy with no IgG4-positive cell infiltrates. A search for circulating immune complexes was negative, and antibodies against M-type phospholipase A(2) receptor could not be detected. Western blot analyses identified circulating IgG3 reacting with superoxide dismutase 2. This case suggests that membranous nephropathy represents an additional renal manifestation of IgG4-related systemic disease, with a pathogenesis possibly associated with neoproduction of autoantibodies targeting podocyte antigen(s).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2011.05.002DOI Listing
August 2011

Renal involvement in Churg-Strauss syndrome.

Am J Kidney Dis 2006 May;47(5):770-9

Dipartimento Area Medica, Azienda Ospedaliera Ospedale San Carlo Borromeo, Milan, Italy.

Background: Churg-Strauss syndrome (CSS) is a rare disorder characterized by asthma, eosinophilia, and systemic vasculitis. Renal involvement is not regarded as a prominent feature, and its prevalence and severity vary widely in published reports that usually refer to small series of selected patients.

Methods: We examined the prevalence, clinicopathologic features, and prognosis of renal disease in 116 patients with CSS.

Results: There were 48 men and 68 women with a mean age of 51.9 years (range, 18 to 86 years). Signs of renal abnormalities were present in 31 patients (26.7%). Rapidly progressive renal insufficiency was documented in 16 patients (13.8%); urinary abnormalities, 14 patients (12.1%); and chronic renal impairment, 1 patient. There were 3 additional cases of obstructive uropathy. Sixteen patients underwent renal biopsy, which showed necrotizing crescentic glomerulonephritis in 11 patients. Other diagnoses were eosinophilic interstitial nephritis, mesangial glomerulonephritis, and focal sclerosis. Antineutrophil cytoplasmic antibody (ANCA) was positive in 21 of 28 patients (75.0%) with nephropathy versus 19 of 74 patients without (25.7%; P < 0.001). In particular, all patients with necrotizing crescentic glomerulonephritis were ANCA positive. After a median follow-up of 4.5 years, 10 patients died (5 patients with nephropathy) and 7 patients developed mild chronic renal insufficiency. Five-year mortality rates were 11.7% (95% confidence interval, 3.9 to 33.3) in patients with nephropathy and 2.7% (95% confidence interval, 0.7 to 10.7) in those without (P = 0.10).

Conclusion: Renal abnormalities are present in about one quarter of patients with CSS. The prevailing picture is ANCA-associated necrotizing crescentic glomerulonephritis; however, other forms of nephropathy also may occur. Outcome and long-term follow-up usually are good.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2006.01.026DOI Listing
May 2006

Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays.

Nephrol Dial Transplant 2006 Feb 18;21(2):397-401. Epub 2005 Oct 18.

Unità Operativa di Immunologia Clinica, Dipartimento Area Medica, Azienda Ospedaliera Ospedale San Carlo Borromeo, Milano, Italy.

Background: The role of anti-glomerular basement membrane (GBM) antibodies in the pathogenesis of Goodpasture syndrome (GPS) is firmly established. Untreated, the disease may follow a fulminating course. Early identification of patients has important implications in terms of management and prognosis. Therefore, a diagnostic test for the determination of circulating anti-GBM antibodies, of very high sensitivity and specificity, is necessary. A number of assays, using different antigenic substrates, are available, but studies comparing the 'performances' of the different tests are scarce.

Methods: The aim of our work was to evaluate the sensitivity and specificity of four immunoassay-based anti-GBM antibodies kits. Thirty-four serum samples from 19 GPS patients, 41 pathological and 28 normal controls were studied retrospectively (the follow-up samples were not included in the analysis of performance data). Cut-off limits were derived from receiver operating characteristics curve analysis.

Results: All the assays showed a comparable good sensitivity (between 94.7 and 100.0%), whereas specificity varied considerably (from 90.9 to 100.0%). The better performance in terms of sensitivity/specificity was achieved by a fluorescence immunoassay which utilizes a recombinant antigen.

Conclusion: All the assays have a good performance, with high sensitivity; however, the specificity may vary considerably.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfi230DOI Listing
February 2006

Value of a new automated fluorescence immunoassay (EliA) for PR3 and MPO-ANCA in monitoring disease activity in ANCA-associated systemic vasculitis.

Ann N Y Acad Sci 2005 Jun;1050:185-92

Dipartimento di Nefrologia e Immunologia, Azienda Ospedaliera, Ospedale San Carlo Borromeo, Via Pio Secondo 3, 20153 Milano, Italy.

The value of anti-neutrophil cytoplasmic antibody (ANCA) detection for monitoring disease activity in ANCA-associated systemic vasculitis (AASV) remains controversial. The aim of our work was to rate the performance of a new automated fluorescence PR3 and MPO-ANCA immunoassay (EliA) for monitoring disease activity in AASV. We evaluated 100 serum samples from 71 AASV patients (with Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome) as well as sera from 58 pathological and 35 normal controls. In addition to PR3 and MPO-ANCA EliA, we performed indirect immunofluorescence and "homemade" PR3 and MPO-ANCA ELISA tests. In AASV patients, ANCA levels were correlated with disease activity, according to the Birmingham Vasculitis Activity Score (BVAS). We derived cutoff limits from receiver operating characteristic (ROC) curve analysis comparing AASV with pathological controls. Our results showed that EliA and ELISA had comparable sensitivity (76%) and specificity (95%). The analysis of active versus inactive status and correlation with ANCA levels showed a clear difference between BVAS Group I (score < or = 4) and BVAS Group II (scores > 4) (AUC = 0.86 vs. 0.72; relative risk [RR] = 2.4; P < 0.0001) for PR3-ANCA, but not for MPO-ANCA (AUC = 0.94 vs. 0.87; RR = 1.48; P = 0.46). Serial serum samples from 16 patients were examined in detail. For the majority of patients, for both PR3 and MPO-ANCA, change in titer was strongly associated with change in BVAS score. Our data showed a good correlation between ANCA titer (especially for PR3) and AASV disease activity. We recommend that ANCA titer be used to monitor AASV disease activity with the caveat that a few exceptions, in particular with MPO-ANCA, are possible.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1196/annals.1313.019DOI Listing
June 2005

Azathioprine hypersensitivity: report of two cases and review of the literature.

J Nephrol 2003 Mar-Apr;16(2):272-6

Unit of Nephrology and Dialysis, Center of Clinical Immunology and Rheumatology, San Carlo Borromeo Hospital, Via Pio Secondo 3, 20153 Milan, Italy.

Azathioprine (AZA) is a widely-used drug in the treatment of different diseases such as vasculitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel diseases and in renal transplantation. Side effects of AZA can be classified as toxic, mainly dose related (myelosuppression and hepatotoxicity) and idiosyncratic, mainly dose independent. While the toxic effects are common and well documented, the hypersensitivity reactions are rare and it is not often easy to distinguish them from systemic sepsis or disease recurrence. We report two cases of AZA hypersensitivity occurring in patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis each mimicking a vasculitis relapse or a septic complication of immunosuppression, as well as a review of the literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2003

The use of laboratory tests in diagnosis and monitoring of systemic lupus erythematosus.

J Nephrol 2002 Nov-Dec;15 Suppl 6:S20-7

Nephrology and Dialysis Unit and Center of Clinical Immunology and Rheumatology, San Carlo Borromeo Hospital, Milan, Italy.

Clinical immunology laboratories play an essential role in diagnosis and monitoring of systemic lupus erythematosus (SLE). To obtain the best results in terms of diagnostic performance and clinical usefulness, the following recommendations should be fulfilled: Indirect immunofluorescence on Hep-2 cells remains the method of choice for the detection of anti-nuclear antibodies (ANA). The sensitivity of ANA test for SLE is very high (almost 100%) but its specificity low since ANA can be present in a number of different clinical conditions and even in normal controls. Anti-dsDNA antibodies are highly specific for SLE and present in a high proportion of SLE patients (40-80%). The method of choice for anti-ds DNA is the Farr assay; however, the necessity of using radioactive material decreases its applicability. As an alternative, immunofluorescence on Crithidia Luciliae can be used in the diagnostic phase for its high specificity. It is not advisable to use ELISA, in the diagnostic phase, due to its low specificity. The quantitative determination of anti-dsDNA is useful for monitoring patients, in particular in the presence of nephritis. For monitoring, a quantitative method should be used (Farr assay or ELISA). The detection of antibodies to extractable nuclear antigens (ENA) and to phospholipids (Lupus anticoagulant and anti-cardiolipin antibodies with a beta2 glycoprotein I-dependent method) are useful to identify subgroups of patients at risk for some clinical manifestations (i.e. anti-phospholipid syndrome). New assays (anti-C1q and anti-nucleosome antibodies) have been recently proposed for diagnosis (anti-nucleosome) and monitoring SLE patients (anti-C1q and anti-nucleosome antibodies), with promising results. Among biological parameters, urinary levels of monocyte chemoattranct protein 1 (MCP1) seem to be the most useful to monitor nephritis activity in lupus patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
April 2003
-->