Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Markowitz, Glen S.; Nasr, Samih H.; Stokes, Michael B.; D’Agati, Vivette D.

doi:10.2215/cjn.07311009

Cited by 204 publications

(187 citation statements)

References 62 publications

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“…2,5,7,10 Endothelial cell TRIs may be induced in vitro and in vivo by type 1 IFNs. [2][3][4][5][6][7] There are three main types of IFNs, which collectively play an important role in both innate and adaptive immunity. IFN-a and IFN-b are the clinically relevant type 1 IFNs, and they are produced predominantly by plasmacytoid dendritic cells and fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

“…After production, IFN-a/b can mediate antiviral and proapoptotic properties and lead to upregulation of proteins involved in the adaptive immune response. 3,[5][6][7] In addition to bacteria and viruses, endogenous RNA or DNA is also a potent inducer of type 1 IFNs, and IFN-a is regarded as the primary cytokine involved in SLE and other autoimmune diseases. 2,3,24,25 Infection remains an important cause of morbidity and mortality post-transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…30,31 Outside of transplantation, it has also been shown that treatment with exogenous IFN-a can produce autoantibodies, leading to a catalog of different autoimmune diseases with native renal pathology. 32 In one case series, Markowitz et al 6 reported 11 patients with collapsing FSGS after treatment with IFN, and 10 of these patients had TRIs. Of interest, a relatively large proportion of our patients who were TRI+ (eight of 41; 19.5%) had FSGS in their biopsy as well.…”

Section: Discussionmentioning

confidence: 99%

“…1,2 TRIs can be induced in endothelial cells both in vitro and in vivo in the context of enhanced type 1 IFN expression. [2][3][4][5][6][7] IFNs are cytokines produced in response to viral infections and in the context of autoimmune disease. 2,5,7 In native renal disease, TRIs in glomerular endothelial cells are most commonly encountered in the setting of SLE and viral infections, especially HIV.…”

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confidence: 99%

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Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies

Willicombe

Moss

Moran

et al. 2015

JASN

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The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy-free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donorspecific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor-specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies

Willicombe

Moss

Moran

et al. 2015

JASN

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“…The pathologic appearance is characterized by global or segmental collapse of the glomerular capillary tuft, with wrinkling and retraction of the capillary walls overlaid by epithelial cell proliferation in the Bowman space that is frequently accompanied by tubulointerstitial disease (1)(2)(3). CG is regarded as a podocytopathy, it is predominantly seen in the primary form in patients of African descent, and it has been associated with numerous etiologies, including viral infections (HIV, cytomegalovirus, Parvovirus B19, and hepatitis C virus), drugs (pamidronate and all forms of IFN), and anecdotally, autoimmune diseases (SLE and mixed connective tissue disease) (4,5). The trigger for the development of CG has been elusive, but an underlying immunemediated mechanism has been postulated in most cases.…”

Section: Introductionmentioning

confidence: 99%

Collapsing Glomerulopathy in 19 Patients with Systemic Lupus Erythematosus or Lupus-Like Disease

Salvatore

Barisoni

Herzenberg

et al. 2012

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Collapsing glomerulopathy is a podocytopathy with segmental or global wrinkling and collapse of capillary walls and overlying epithelial cell proliferation. Idiopathic collapsing glomerulopathy is a distinct clinicopathologic entity with significant proteinuria, poor response to immunosuppressive therapy, and rapid progression to renal failure. Collapsing glomerulopathy is associated with viral infections, autoimmune disease, and drugs. This work presents the largest group of collapsing glomerulopathy in patients with SLE.Design, setting, participants, & measurements Clinicopathological features were retrospectively studied in 19 patients with SLE (16 patients) or SLE-like (3 patients) disease with collapsing glomerulopathy.Results Initially, 95% of patients had nephrotic syndrome with proteinuria of 3-12 g per 24 hours, creatinine levels of 0.6-9.6 mg/dl, positive lupus serologies, and normal complement levels in 63%. Segmental and/or global collapsing glomerulopathy was seen in 11%-77% of glomeruli. Tubular atrophy with focal microcystic changes and interstitial fibrosis was seen in 35% of patients. Minimal glomerular mesangial deposits were noted in 63% of patients, and extensive foot process effacement was seen in 82% of patients. Initial treatment was with pulse/oral steroids. Follow-up from 13 patients revealed that 7 patients progressed to ESRD at the time of biopsy up to 21 months later, 1 patient returned to normal creatinine (1.1 mg/dl) without proteinuria, and 5 patients had creatinine of 1.2-3.6 mg/dl with proteinuria of 0.37-4 g per 24 hours.Conclusions Collapsing glomerulopathy may be seen in SLE patients presenting with massive proteinuria with or without lupus nephritis, which may have prognostic significance.

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Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria

et al. 2013

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The mechanisms by which inflammation or autoimmunity causes proteinuric kidney disease remain elusive. Yet proteinuria is a hallmark and a prognostic indicator of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Podocytes are an integral component of the kidney filtration barrier and podocyte injury leads to proteinuria. Here we show that podocytes, which receive signals from the vascular space including circulating antigens, constitutively express TLR1–6 and TLR8. We find that podocytes can respond to TLR ligands including staphylococcal enterotoxin B (SEB), poly I:C, or lipopolysaccharide (LPS) with pro-inflammatory cytokine release and activation of type I interferon (IFN) signalling. This in turn stimulates podocyte B7-1 expression and actin remodelling in vitro and transient proteinuria in vivo. Importantly, the treatment of mice with a type I IFN receptor-blocking antibody (Ab) prevents LPS-induced proteinuria. These results significantly extend our understanding of podocyte response to immune stimuli and reveal a novel mechanism for infection- or inflammation-induced transient proteinuria. Dysregulation or aberrant activation of this response may result in persistent proteinuria and progressive glomerular disease. In summary, the inhibition of glomerular type I IFN signalling with anti-IFN Abs may be a novel therapy for proteinuric kidney diseases.

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Treatment with IFN-α, -β, or -γ Is Associated with Collapsing Focal Segmental Glomerulosclerosis

Cited by 204 publications

References 62 publications

Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies

Tubuloreticular Inclusions in Renal Allografts Associate with Viral Infections and Donor-Specific Antibodies

Collapsing Glomerulopathy in 19 Patients with Systemic Lupus Erythematosus or Lupus-Like Disease

Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria

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