Urinary CD80: a biomarker for a favorable response to corticosteroids in minimal change disease.

Minimal Change Disease (MCD) is the most common type of nephrotic syndrome in children. The etiology has remained unknown, although it is commonly thought to be due to an unknown circulating factor that triggers podocyte dysfunction. To date, several changes in podocytes have been reported in MCD, of which one is the expression of CD80, also known as B7.1, which is a costimulatory molecule that is normally expressed on antigen -presenting cells. Some studies suggest that subjects with steroid-sensitive MCD may express CD80 in their podocytes during relapse and that this expression is associated with high urinary levels of CD80. Indeed, subjects with MCD in remission, or subjects with other glomerular diseases, such as focal segmental glomerulosclerosis, have substantially lower levels of urinary CD80 excretion. A recent study has now reported that high levels of urinary CD80 may be a sensitive marker for steroid-sensitivity and that their presence is also associated with long-term preservation of renal function. Thus, urinary CD80 is emerging as a potential biomarker for steroid-responsiveness in children presenting with primary nephrotic syndrome.

ß1-Integrin blockade prevents podocyte injury in experimental models of minimal change disease.

INTRODUCTION: Activation of the focal adhesion kinase (FAK) in podocytes is involved in the pathogenesis of minimal change disease (MCD), but the pathway leading to its activation in this disease is unknown. Here, we tested whether podocyte ß1 integrin is the upstream modulator of FAK activation and podocyte injury in experimental models of MCD-like injury. METHODS: We used lipopolysaccharide (LPS) and MCD sera to induce MCD-like changes in vivo and in cultured human podocytes, respectively. We performed functional studies using specific ß1 integrin inhibitors in vivo and in vitro, and integrated histological analysis, western blotting, and immunofluorescence to assess for morphological and molecular changes in podocytes. By ELISA, we measured serum LPS levels in 35 children with MCD or presumed MCD (idiopathic nephrotic syndrome [INS]) and in 18 healthy controls. RESULTS: LPS-injected mice showed morphological (foot process effacement, and normal appearing glomeruli on light microscopy) and molecular features (synaptopodin loss, nephrin mislocalization, FAK phosphorylation) characteristic of human MCD. Administration of a ß1 integrin inhibitor to mice abrogated FAK phosphorylation, and ameliorated proteinuria and podocyte injury following LPS. Children with MCD/INS in relapse had higher serum LPS levels than controls. In cultured human podocytes, ß1 integrin blockade prevented cytoskeletal rearrangements following exposure to MCD sera in relapse. CONCLUSIONS: Podocyte ß1 integrin activation is an upstream mediator of FAK phosphorylation and podocyte injury in models of MCD-like injury.

Effect of galactose on glomerular permeability and proteinuria in steroid-resistant nephrotic syndrome.

BACKGROUND: Idiopathic steroid-resistant nephrotic syndrome (SRNS) has been associated with the presence of a circulating focal sclerosis permeability factor (FSPF) thought to damage the glomerular barrier and increase permeability to albumin. Galactose binds and inactivates FSPF in vitro, but its effect in vivo is uncertain. METHODS: A prospective clinical trial was conducted to investigate the effect of oral galactose on FSPF and proteinuria in children with SRNS. Seven pediatric subjects with idiopathic SRNS and positive FSPF activity (>0.5) were treated with oral galactose (0.2 gm/kg/dose twice daily) for 16 weeks. Post-treatment FSPF and proteinuria were measured. RESULTS: Focal sclerosis permeability factor activity of the seven subjects decreased from 0.69 ± 0.11 to 0.35 ± 0.21 (p = 0.009) in response to galactose. The two subjects with post-transplant recurrence of focal segmental glomerulosclerosis (FSGS) demonstrated the most significant improvement in FSPF (p = 0.006). Despite this decrease in FSPF, the pre- and post-treatment urine protein:creatinine ratio remained unchanged and no subject achieved remission. CONCLUSIONS: Galactose decreases FSPF in children with SRNS, with the most significant improvement in those with post-transplant FSGS recurrence, but it fails to improve proteinuria. At the present time there is no evidence to support the use of galactose in children with FSGS, either pre- or post-transplant. Future studies to investigate the role of galactose as preemptive therapy to decrease the risk of post-transplant FSGS recurrence may be useful.

Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood.

Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.

Minimal Change Disease Is Associated With Endothelial Glycocalyx Degradation and Endothelial Activation.

Introduction: Minimal change disease (MCD) is considered a podocyte disorder triggered by unknown circulating factors. Here, we hypothesized that the endothelial cell (EC) is also involved in MCD. Methods: We studied 45 children with idiopathic nephrotic syndrome (44 had steroid sensitive nephrotic syndrome [SSNS], and 12 had biopsy-proven MCD), 21 adults with MCD, and 38 healthy controls (30 children, 8 adults). In circulation, we measured products of endothelial glycocalyx (EG) degradation (syndecan-1, heparan sulfate [HS] fragments), HS proteoglycan cleaving enzymes (matrix metalloprotease-2 [MMP-2], heparanase activity), and markers of endothelial activation (von Willebrand factor [vWF], thrombomodulin) by enzyme-linked immunosorbent assay (ELISA) and mass spectrometry. In human kidney tissue, we assessed glomerular EC (GEnC) activation by immunofluorescence of caveolin-1 (n = 11 MCD, n = 5 controls). In vitro, we cultured immortalized human GEnC with sera from control subjects and patients with MCD/SSNS sera in relapse (n = 5 per group) and performed Western blotting of thrombomodulin of cell lysates as surrogate marker of endothelial activation. Results: In circulation, median concentrations of all endothelial markers were higher in patients with active disease compared with controls and remained high in some patients during remission. In the MCD glomerulus, caveolin-1 expression was higher, in an endothelial-specific pattern, compared with controls. In cultured human GEnC, sera from children with MCD/SSNS in relapse increased thrombomodulin expression compared with control sera. Conclusion: Our data show that alterations involving the systemic and glomerular endothelium are nearly universal in patients with MCD and SSNS, and that GEnC can be directly activated by circulating factors present in the MCD/SSNS sera during relapse.

Vasculitis in a Child With the Hyper-IgM Variant of Ataxia-Telangiectasia.

A subset of patients with Ataxia-Telangiectasia (A-T) have dramatically reduced levels of IgG, IgA, and IgE with retained or elevated IgM levels. Several reports suggest that these A-T patients with a "hyper-IgM phenotype" (HIgM) suffer more clinical immunologic consequences than other A-T patients. The immunopathologic mechanism driving this phenomenon is unknown, making it difficult to predict response to immunomodulatory therapy. We describe an A-T patient with HIgM who underwent tumor necrosis factor (TNF) receptor blockade for cutaneous granuloma and after several months of successful therapy developed non-malignant lymphoproliferation, cytopenia, and increased serum immunoglobulin levels. This process was subsequently followed by an immune-complex-mediated intrarenal small vessel vasculitis that led to renal failure. The vasculitis was successfully treated with rituximab and corticosteroids. This case underscores the importance of HIgM as an unfavorable prognostic indicator in A-T and highlights the complexity of immunomodulatory treatment in this population, and the potential for a successful approach tailored to the immune defect.