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Thomas L Nickolas,
Catherine S Forster,
Meghan E Sise,
Nicholas Barasch,
David Solá-Del Valle,
Melanie Viltard,
Charles Buchen,
Shlomo Kupferman,
Maria Luisa Carnevali,
Michael Bennett, Silvia Mattei,
Achiropita Bovino,
Lucia Argentiero,
Andrea Magnano,
Prasad Devarajan,
Kiyoshi Mori,
Hediye Erdjument-Bromage,
Paul Tempst,
Landino Allegri,
Jonathan Barasch
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ABSTRACT: The type and the extent of tissue damage inform the prognosis of chronic kidney disease (CKD), but kidney biopsy is not a routine test. Urinary tests that correlate with specific histological findings might serve as surrogates for the kidney biopsy. We used immunoblots and ARCHITECT-NGAL assays to define the immunoreactivity of urinary neutrophil gelatinase-associated lipocalin (NGAL) in CKD, and we used mass spectroscopy to identify associated proteins. We analyzed kidney biopsies to determine whether specific pathological characteristics associated with the monomeric NGAL species. Advanced CKD urine contained the NGAL monomer as well as novel complexes of NGAL. When these species were separated, we found a significant correlation between the NGAL monomer and glomerular filtration rate (r=-0.53, P<0.001), interstitial fibrosis (mild vs. severe disease; mean 54 vs. 167 μg uNGAL/g Cr, P<0.01), and tubular atrophy (mild vs. severe disease; mean 54 vs. 164 μg uNGAL/g Cr, P<0.01). Monospecific assays of the NGAL monomer demonstrated a correlation with histology that typifies progressive, severe CKD.Kidney International advance online publication, 13 June 2012; doi:10.1038/ki.2012.195.
Kidney International 06/2012; · 6.61 Impact Factor
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Marco Prunotto,
Maria Luisa Carnevali,
Giovanni Candiano,
Corrado Murtas,
Maurizio Bruschi,
Emilia Corradini,
Antonella Trivelli,
Alberto Magnasco,
Andrea Petretto,
Laura Santucci, Silvia Mattei,
Rita Gatti,
Francesco Scolari,
Peter Kador,
Landino Allegri,
Gian Marco Ghiggeri
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ABSTRACT: Glomerular targets of autoimmunity in human membranous nephropathy are poorly understood. Here, we used a combined proteomic approach to identify specific antibodies against podocyte proteins in both serum and glomeruli of patients with membranous nephropathy (MN). We detected specific anti-aldose reductase (AR) and anti-manganese superoxide dismutase (SOD2) IgG(4) in sera of patients with MN. We also eluted high titers of anti-AR and anti-SOD2 IgG(4) from microdissected glomeruli of three biopsies of MN kidneys but not from biopsies of other glomerulonephritides characterized by IgG deposition (five lupus nephritis and two membranoproliferative glomerulonephritis). We identified both antigens in MN biopsies but not in other renal pathologies or normal kidney. Confocal and immunoelectron microscopy (IEM) showed co-localization of anti-AR and anti-SOD2 with IgG(4) and C5b-9 in electron-dense podocyte immune deposits. Preliminary in vitro experiments showed an increase of SOD2 expression on podocyte plasma membrane after treatment with hydrogen peroxide. In conclusion, our data support AR and SOD2 as renal antigens of human MN and suggest that oxidative stress may drive glomerular SOD2 expression.
Journal of the American Society of Nephrology 02/2010; 21(3):507-19. · 9.66 Impact Factor
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Neal Paragas,
Thomas L Nickolas,
Christina Wyatt,
Catherine S Forster,
Meghan Sise,
Susan Morgello,
Bernd Jagla,
Charles Buchen,
Peter Stella,
Simone Sanna-Cherchi, [......],
Achiropita Bovino,
Lucia Argentiero,
Andrea Magnano,
Prasad Devarajan,
Kai M Schmidt-Ott,
Landino Allegri,
Paul Klotman,
Vivette D'Agati,
Ali G Gharavi,
Jonathan Barasch
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ABSTRACT: Nephrosis and a rapid decline in kidney function characterize HIV-associated nephropathy (HIVAN). Histologically, HIVAN is a collapsing focal segmental glomerulosclerosis with prominent tubular damage. We explored the expression of neutrophil gelatinase-associated lipocalin (NGAL), a marker of tubular injury, to determine whether this protein has the potential to aid in the noninvasive diagnosis of HIVAN. We found that expression of urinary NGAL was much higher in patients with biopsy-proven HIVAN than in HIV-positive and HIV-negative patients with other forms of chronic kidney disease. In the HIV-transgenic mouse model of HIVAN, NGAL mRNA was abundant in dilated, microcystic segments of the nephron. In contrast, urinary NGAL did not correlate with proteinuria in human or in mouse models. These data show that marked upregulation of NGAL accompanies HIVAN and support further study of uNGAL levels in large cohorts to aid in the noninvasive diagnosis of HIVAN and screen for HIVAN-related tubular damage.
Journal of the American Society of Nephrology 09/2009; 20(8):1687-92. · 9.66 Impact Factor
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Simone Sanna-Cherchi,
Maria Luisa Carnevali,
Davide Martorana,
Paolo Cravedi,
Umberto Maggiore,
Rossella Alinovi,
Achiropita Bovino, Silvia Mattei,
Guido Orlandini,
Rita Gatti,
Mario Savi,
Yoshikazu Sado,
Tauro M Neri,
Landino Allegri
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ABSTRACT: Type IV collagen is a major structural component of the normal kidney glomerulus. However, its role in chronic acquired glomerulopathies has been only partially elucidated.
Urinary levels of col(IV)alpha1, col(IV)alpha3 and col(IV)alpha5 collagen chains were analyzed in 107 patients with chronic acquired glomerulopathies. In a subgroup of 33 patients, tissue mRNA levels, protein expression and urinary excretion were evaluated for all col(IV)alpha chains, from col(IV)alpha1 to col(IV)alpha5. The renal specimens were examined to get a semiquantitative score of the acute and chronic activity of the histological lesions. Urines obtained from 13 healthy subjects and 10 normal renal tissue samples were used as controls.
Urinary levels of col(IV)alpha1, col(IV)alpha3, col(IV)alpha5 chains were significantly higher in patients than in controls [p < 0.01 for all], while only col(IV)alpha1 and col(IV)alpha3 urinary excretion correlated with the degree of chronic histological damage [col(IV)alpha1 R = 0.44, p < 0.001; col(IV)alpha3: R = 0.47, p < 0.001]. Compared with controls, patients showed a renal expression of mRNA for col(IV)alpha5 chain significantly higher [p = 0.001], while having a significantly lower protein expression of col(IV)alpha3, col(IV)alpha4 and col(IV)alpha5 chains [p < 0.01 for all].
Patients with chronic acquired glomerulopathies show important alterations in the col(IV)alpha chain network mimicking some molecular features of the X-linked Alport's syndrome. Further studies are needed to show whether urinary levels of the col(IV)alpha chains may be used as markers for monitoring renal injury.
American Journal of Nephrology 01/2007; 27(2):129-37. · 2.54 Impact Factor
