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Maria V Irazabal,
Alfonso Eirin,
John Lieske, Laurence H Beck,
Sanjeev Sethi,
Timothy M Borland,
John J Dillon,
Patrick H Nachman,
Samih H Nasr,
Lynn D Cornell,
Nelson Leung,
Daniel C Cattran,
Fernando C Fervenza
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ABSTRACT: BACKGROUND: Selective urinary biomarkers have been considered superior to total proteinuria in predicting response to treatment and outcome in patients with membranous nephropathy (MN). METHODS: We prospectively tested whether urinary (U) excretion of retinol-binding protein (RBP), α1-microglobulin (α1M), albumin, immunoglobulinIgG and IgM and/or anti-phospholipase 2 receptor (PLA(2)R) levels could predict response to rituximab (RTX) therapy better than standard measures in MN. We also correlated changes in antibodies to PLA(2)R with these urinary biomarkers. RESULTS: Twenty patients with MN and proteinuria (P) >5 g/24 h received RTX (375 mg/m(2) × 4) and at 12 months, 1 patient was in complete remission (CR), 9 were in partial remission (PR), 5 had a limited response (LR) and 4 were non-responders (NR). At 24 months, CR occurred in 4, PR in 12, LR in 1, NR in 2 and 1 patient relapsed. By simple linear regression analysis, UIgG at baseline (mg/24 h) was a significant predictor of change in proteinuria at 12 months (Δ urinary protein) (P = 0.04). In addition, fractional excretion (FE) of IgG, urinary alpha 1 microglobulin (Uα1M) (mg/24 h) and URBP (μg/24 h) were also predictors of response (P = 0.05, 0.04, and 0.03, respectively). On the other hand, UIgM, FEIgM, albumin and FE albumin did not predict response (P = 0.10, 0.27, 0.22 and 0.20, respectively). However, when results were analyzed in relation to proteinuria at 24 months, none of the U markers that predicted response at 12 m could predict response at 24 m (P = 0.55, 0.42, 0.29 and 0.20). Decline in anti-PLA(2)R levels was associated with and often preceded urinary biomarker response but positivity at baseline was not a predictor of proteinuria response. CONCLUSIONS: The results suggest that in patients with MN, quantification of low-, medium- and high-molecular-weight urinary proteins may be associated with rate of response to RTX, but do not correlate with longer term outcomes.
Nephrology Dialysis Transplantation 09/2012; · 3.40 Impact Factor
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ABSTRACT: Antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) have been demonstrated to mediate anti-neutrophil cytoplasmic antibody (ANCA)-associated disease. For membranous nephropathy, antibodies to the podocyte-expressed phospholipase A(2) receptor (anti-PLA(2)R) are highly associated with disease activity and have been reported in at least 70% of patients with idiopathic membranous nephropathy (IMN). We present a case of a 56-year-old male with a 1 year history of hypertension, leg edema, and proteinuria, who presented with advanced renal failure and was found to have both ANCA-associated glomerulonephritis (GN) and IMN on kidney biopsy. Consistent with the idea that this is due to the chance occurrence of two independent diseases, we found both anti-MPO and anti-PLA(2)R antibodies in the patient's sera. Treatment with methylprednisolone, plasmapheresis, and cyclophosphamide resulted in improvement in kidney function and proteinuria, together with the simultaneous decrease in both autoantibodies. This is the first demonstration of two pathogenic antibodies giving rise to ANCA-associated GN and IMN in the same patient. It confirms the importance of classifying disease based upon the underlying mechanism, in addition to renal histopathology, to both optimize therapy and predict prognosis.
Clinical kidney journal. 04/2012; 5(2):162-165.
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Laurence H Beck
American Journal of Kidney Diseases 02/2012; 59(2):174-6. · 5.43 Impact Factor
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ABSTRACT: Patients with IgG4-related disease (IgG4-RD) share histopathological characteristics that are similar across affected organs. The finding of infiltration with IgG4+ plasma cells in the proper clinical and histopathological contexts connects a large number of clinical entities that were viewed previously as separate conditions. The renal involvement in IgG4-RD is usually characterized by tubulointerstitial nephritis, but membranous nephropathy has also been reported to be one of the renal complications of IgG4-RD. The recent discovery that a high proportion of patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies to the M-type phospholipase A2 receptor (PLA2R) in the circulation and glomerular immune deposits, together with the profound IgG4 hypergammaglobulinemia and occasional reports of membranous nephropathy in IgG4-RD, raised the question of a common antigen. To assess the presence of anti-PLA2R antibody in patients with IgG4-RD, we screened sera from 28 IgG4-RD patients by immunoblot. None of the patients in this cohort had detectable circulating anti-PLA2R antibodies. This study suggests that despite some clinical and serological overlaps between IgG4-RD and IMN,anti-PLA2R antibodies do not play a role in the pathogenesis of IgG4-RD. Additional studies of IgG4-RD with evidence of membranous nephropathy are important to exclude any definite relationship.
International Journal of Rheumatology 01/2012; 2012:139409.
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ABSTRACT: Autoantibodies to the M-type phospholipase A(2) receptor (PLA(2)R) are sensitive and specific for idiopathic membranous nephropathy. The anti-B cell agent rituximab is a promising therapy for this disease, but biomarkers of early response to treatment currently do not exist. Here, we investigated whether levels of anti-PLA(2)R correlate with the immunological activity of membranous nephropathy, potentially exhibiting a more rapid response to treatment than clinical parameters such as proteinuria. We measured the amount of anti-PLA(2)R using Western blot immunoassay in serial serum samples from a total of 35 patients treated with rituximab for membranous nephropathy in two distinct cohorts. Pretreatment samples from 25 of 35 (71%) patients contained anti-PLA(2)R, and these autoantibodies declined or disappeared in 17 (68%) of these patients within 12 months after rituximab. Those who demonstrated this immunologic response fared better clinically: 59% and 88% attained complete or partial remission by 12 and 24 months, respectively, compared with 0% and 33% among those with persistent anti-PLA(2)R levels. Changes in antibody levels preceded changes in proteinuria. One subject who relapsed during follow-up had a concomitant return of anti-PLA(2)R. In summary, measuring anti-PLA(2)R levels by immunoassay may be a method to follow and predict response to treatment with rituximab in membranous nephropathy.
Journal of the American Society of Nephrology 08/2011; 22(8):1543-50. · 9.66 Impact Factor
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ABSTRACT: We describe a 67-year-old woman who presented with significant proteinuria and hematuria. Kidney biopsy showed immunoglobulin G4 (IgG4)-related tubulointerstitial nephritis (TIN) with concurrent membranous nephropathy. IgG4-related TIN is a recently described entity that presents with progressive decreased kidney function and is characterized by a plasma cell-rich infiltrate that is positive for IgG4. It is associated with patchy, often well-localized, tubular atrophy and interstitial fibrosis. Workup for circulating anti-phospholipase A(2) receptor antibodies was negative, suggesting that the membranous nephropathy was not "primary" and may be linked to the IgG4-related disease. The presence of significant proteinuria and hematuria in the setting of IgG4-related TIN should raise suspicion of a glomerular disease. It is important to correctly diagnose IgG4-related TIN and concurrent membranous nephropathy because the lesion responds well to steroid therapy.
American Journal of Kidney Diseases 06/2011; 58(2):320-4. · 5.43 Impact Factor
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Paolo Cravedi,
Mauro Abbate,
Elena Gagliardini,
Miriam Galbusera,
Simona Buelli,
Ettore Sabadini,
Maddalena Marasà, Laurence H Beck,
David J Salant,
Ariela Benigni,
Vivette D'Agati,
Giuseppe Remuzzi
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ABSTRACT: 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).
American Journal of Kidney Diseases 06/2011; 58(2):272-5. · 5.43 Impact Factor
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ABSTRACT: Circulating autoantibodies against the M-type phospholipase A(2) receptor (anti-PLA(2)R) were recently identified in the majority of patients in the United States with idiopathic membranous nephropathy (iMN). The objectives of this study were to assess the prevalence of anti-PLA(2)R in a separate, European cohort of iMN patients and to correlate the presence of anti-PLA(2)R with clinical parameters reflective of disease activity.
Anti-PLA(2)R levels were blindly assessed by a Western blot immunoassay in 54 serum samples from 18 patients with iMN collected in various stages of clinical disease. Anti-PLA(2)R levels were correlated with other clinical parameters.
77.8% of iMN patients in our cohort had antibodies reactive with human PLA(2)R. The antibody levels in these patients correlated strongly with both clinical status and proteinuria (r = 0.73, P < 0.01).
The role of PLA(2)R as a major antigen in iMN was confirmed in an independent, European patient cohort, and levels of circulating anti-PLA(2)R revealed a strong correlation with clinical disease activity. We propose that detection and measurement of these autoantibodies may provide a tool for monitoring of disease activity and treatment efficacy.
Clinical Journal of the American Society of Nephrology 06/2011; 6(6):1286-91. · 5.23 Impact Factor
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ABSTRACT: The M-type phospholipase A2 receptor (PLA2R) is a target autoantigen in adult idiopathic membranous nephropathy (MN), but the prevalence of autoantibodies against PLA2R is unknown among Chinese patients with MN. Here, we measured anti-PLA2R antibody in the serum of 60 patients with idiopathic MN, 20 with lupus-associated MN, 16 with hepatitis B (HBV)-associated MN, and 10 with tumor-associated MN. Among patients with idiopathic MN, 49 (82%) had detectable anti-PLA2R autoantibodies using a Western blot assay; an assay with greater sensitivity detected very low titers of anti-PLA2R in 10 of the remaining 11 patients. Using the standard assay, we detected anti-PLA2R antibody in only 1 patient with lupus, 1 with HBV, and 3 with cancer, producing an overall specificity of 89% in this cohort limited to patients with secondary MN. The enhanced assay detected low titers of anti-PLA2R in only 2 additional samples of HBV-associated MN. In summary, these results suggest that PLA2R is a major target antigen in Chinese idiopathic MN and that detection of anti-PLA2R is a sensitive test for idiopathic MN.
Journal of the American Society of Nephrology 06/2011; 22(6):1137-43. · 9.66 Impact Factor
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ABSTRACT: To determine which nephron segments require Notch signals for development, we conditionally deleted Rbpj, a transcription factor required for canonical Notch signaling, in nephrogenic progenitors (NPs) of the metanephric mesenchyme. The retinoic acid receptor-β2 (Rarb2) promoter efficiently directed Cre-recombinase (Cre) activity to these progenitors. Conditional knockout of Rbpj in mice (Rarb2Cre(+)/Rbpj (f/-)) caused severe renal hypoplasia, as indicated by a 70-95% reduction in nephron number and the development of tubular cysts. To track the fate of NPs following Rarb2Cre expression, we labeled them with membrane-associated enhanced green fluorescent protein (GFP). In TomatoGFP(+)/Rarb2Cre(+) control mice, NPs differentiated into epithelia of all nephron segments, except into collecting ducts. In TomatoGFP(+)/Rarb2Cre(+)/Rbpj (f/-) conditional knockout mice, NPs developed into podocytes or distal tubular epithelia, indicating that canonical Notch signals were not required for mesenchymal-to-epithelial transition or for the specification of these nephron segments. Conversely, the few proximal tubules and associated cysts that developed in these mice were derived from the 5-10% of NPs that had failed to express Cre and, therefore, had intact Notch signaling. Thus, our fate mapping studies establish that the profound effect of Notch signaling on nephrogenesis is due to the specification of proximal but not distal tubules or podocytes.
Kidney International 01/2011; 79(10):1099-112. · 6.61 Impact Factor
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Laurence H Beck
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ABSTRACT: An association between the glomerular disease membranous nephropathy (MN) and malignancy has long been appreciated, but evidence supporting this relationship remains limited, speculative, and, at times, controversial. Reports that the two disease processes often evolve in parallel, as well as the occasional findings of tumor antigens or tumor-reactive antibodies within glomerular immune deposits, are all supportive of an association. However, the diagnosis of both MN and malignancy in the same individual also may be coincidental, especially in an older demographic group in which both diseases tend to occur. This article briefly reviews the proposed pathogenetic mechanisms of idiopathic and secondary forms of MN, as well as the arguments for and against the contention that malignancy-associated MN is itself a distinct clinical entity. In addition, the recent identification of the M-type phospholipase A₂ receptor as a major glomerular antigen in idiopathic MN has the potential to offer fresh tools that might help resolve some of the controversy, and ultimately aid in the decision of how aggressively to screen for malignancy in an individual diagnosed with MN.
Seminars in Nephrology 11/2010; 30(6):635-44. · 2.12 Impact Factor
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ABSTRACT: Insights from experimental studies have been recently translated into substantial advances in understanding the pathogenesis of human membranous nephropathy (MN). These include identification of neutral endopeptidase (NEP) as the target antigen in alloimmune MN resulting from fetomaternal immunization in NEP-deficient mothers, and our demonstration that a high proportion of patients with idiopathic MN (IMN) have circulating antibodies to the M-type phospholipase A2 receptor (PLA2R), a transmembrane protein located on podocytes. Here we highlight the studies that led to these discoveries and our current knowledge about the possible role of anti-PLA2R autoantibodies in the pathogenesis of IMN. Given that the sensitivity and specificity of anti-PLA2R for IMN are >75 and 100%, respectively, we foresee that a widely available assay for anti-PLA2R will prove to be valuable for diagnosing IMN, distinguishing it from secondary MN, and evaluating response to therapy. We suggest reasons why 25% of patients with IMN have tested negative for anti-PLA2R, and propose possible explanations for the presence of complement deposits in IMN despite the fact that immunoglobulin G4 (IgG4), the predominant anti-PLA2R IgG subclass, is incapable of activating the classical complement pathway. Finally, we point out avenues to be explored, including the events that induce production of anti-PLA2R, their ability to cause podocyte injury, the role of complement, and the nature of the antibodies in secondary forms of MN.
Kidney International 02/2010; 77(9):765-70. · 6.61 Impact Factor
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ABSTRACT: Idiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown.
We performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody.
Serum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA(2)R.
A majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease.
New England Journal of Medicine 08/2009; 361(1):11-21. · 53.30 Impact Factor
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Journal of the American Society of Nephrology 05/2009; 20(4):690-1. · 9.66 Impact Factor
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ABSTRACT: This article provides a general overview of some of the more common or illustrative glomerular and tubulointerstitial disorders encountered in clinical practice. Disorders are grouped into those causing the nephrotic syndrome, the acute nephritic syndrome and rapidly progressive glomerulonephritis (RPGN), and chronic tubulointerstitial disease. This division is useful for narrowing the differential diagnosis and deciding on further testing and management. Elements of the past history, including detailed family, medication, and social histories, and recent symptoms and physical examination findings are as much a part of the diagnostic workup as are urinary and blood tests. An assessment of the tempo and severity of renal deterioration is critical to separate potential medical emergencies, such as RPGN, from those more indolent disorders that can be managed by the primary care physician.
Primary Care Clinics in Office Practice 07/2008; 35(2):265-96, vi. · 1.01 Impact Factor
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Annals of the New York Academy of Sciences 12/2006; 149(1):539 - 543. · 3.15 Impact Factor
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ABSTRACT: The vascular endothelium in vivo is a remarkably quiescent cell layer that displays a highly differentiated and tissue-specific phenotype. Once established in culture, endothelial cells (EC) are phenotypically different from their in situ counterparts, displaying altered gene expression, increased mitotic index, and decreased cell density. To determine whether manipulating the microenvironment of cells in vitro would lead to a more differentiated phenotype, we cultured bovine aortic EC on floating collagen gels. EC cultured to confluence on floating gels for 24 or 48 hr display mitotic indices nearly identical to those of quiescent endothelium in vivo, nearly two log orders lower than that of EC cultured to confluence on plastic, and cell density on floating gels also resembles that observed for endothelium in vivo. Culture of EC on floating gels leads to decreased expression of platelet-derived growth factor-B, fibronectin, and fibronectin isoform ED-B, and increased levels of connexin40, relative to cells cultured on plastic. We conclude that culture of bovine aortic EC under standard culture conditions results in a phenotype reminiscent of development and/or wound healing, and that culturing them on a floating collagen gel leads to a more differentiated phenotype, reminiscent of that observed for large vessel EC in vivo.
Differentiation 05/2004; 72(4):162-70. · 2.81 Impact Factor
