The Zenith Syndrome
In addition, circulating antibodies to cryptic, conformational epitopes within the NC1 domain of the alpha 3 chain of Type IV Collagen are commonly found at the zenith of the clinical disease.http://theranchhands.com/images/diaries/writing-101-for-beginners.php
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However, exceptions to these general rules do occur, as exemplified by two remarkable cases reported in this issue of the Clinical Kidney Journal. The possible explanations for and the lessons learned from these uncommon occurrences are discussed in this short commentary. Anti-glomerular basement membrane GBM antibody disease is an uncommon but very well understood autoimmune disease, first delineated by Lerner, Glassock and Dixon in [ 1 ]. It has been known for over two decades that the predominant pathogenic autoantibody is of the IgG isotype and is directed to epitopes on the non-collagenous NC domain of Type IV collagen, chiefly, but not exclusively, in a peptide sequence of the alpha 3 chain [ 2 , 3 ].
The two major epitopes Ea and Eb are cryptic and conformational, residing in the hexamer of the alpha 3, 4, 5 chains of Type IV collagen [ 2 ]. Dissolution of sulfilimine bonds and dissociation of the hexamer are required for binding of anti-GBM autoantibodies [ 4 ]. A large number of assays for such autoantibodies have been developed and described, some having commercial applications, while others are primarily of research interest [ 6 — 11 ]. These assays utilize a variety of basement membrane substrates and detection technology [e.
A highly sensitive bio-sensor assay has also recently been described, but is generally not available for clinical use [ 6 ]. Such cases may be detected by IIF [ 8 ]. Furthermore, it is well known that the anti-GBM antibodies in human disease are intrinsically heterogeneous with respect to their reactivity to GBM constituents, but only some anti-GBM antibodies are pathogenic [ 2 , 8 , 13 , 14 ]. The origin of this heterogeneity is uncertain, but might be due to secondary release of altered or cryptic autoantigens from damaged tissue or due to intra- or intermolecular epitope spreading in evolving disease [ 15 ].
Importantly, the assays for anti-GBM antibody utilize a variety of substrates: Thus, the origins of the false-negative results are potentially quite varied. To summarize, they include: These largely anecdotal reports have led to the suggestion that no single test can replace the accuracy of a good quality kidney biopsy and a nephrologist's clinical acumen in diagnosing Goodpasture's disease now known generally as anti-GBM disease [ 18 ]. Of course, a positive anti-GBM assay performed in a respected laboratory has a very high predictive value, in a clinically compatible scenario, approaching It then naturally subsides, often over a protracted period without specific treatment, leaving behind a variable degree of lasting glomerular injury, depending on the magnitude of the initial injury, the timeliness and aggressiveness of treatment, most often associated with the disappearance of circulating anti-GBM antibodies [ 21 , 22 ].
Atypical forms of presumed anti-GBM disease not associated with crescentic GN have been described [ 25 ]. The precise mechanisms underlying this uncommon recurring and relapsing form of anti-GBM disease are obscure, but T-cell-mediated modulation of the immune response has been suggested, based on experimental studies of animal models of the disease [ 16 ]. Both of these phenomena are described in two exceptional case reports published in this issue of the Clinical Kidney Journal by Liu et al.
No pulmonary hemorrhage PH was observed initially. The patient subsequently experienced two relapses, one 5 years after the initial episode, this time with PH and positive anti-GBM. She was treated with PLEX, steroids and cyclophosphamide, the latter for 32 months—a period greatly exceeding usual practice. She improved with treatment and no further relapses have occurred despite continued cigarette smoking.
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Standard therapy again improved the PH, but she was left dialysis-dependent. Like the case of Liu et al. Taken together, these two cases provide an important lesson that a monophasic illness is not inevitable in anti-GBM disease, and detection of anti-GBM antibodies can be quite variable depending on the assay used.
These observations extend the phenotype of antic-GBM disease. A common feature in these two cases is the continuing exposure to pulmonary irritants and prominent manifestations of PH with relapses. This might explain the repeated bouts of PH in the presence of a low and undetectable by conventional assays levels of possibly low-affinity anti-GBM antibodies.
These antibodies might have been detected by WB or bio-sensor-based assays, which were not performed. The continued presence of linear deposits of IgG in the case of Gu et al. WB or chemiluminescence assays are preferred when the ELISA assays are inextricably negative; however, these assays may be of limited availability.
Periprocedural morbidity included temporary renal failure in 1 patient and postimplantation syndrome with fever and leukocytosis for 23 days in 1 patient. No cases of paraplegia were recorded.
No migration of the device was observed. No late occlusion of the visceral or renal arteries was recorded at follow-up.
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The zenith syndrome / Robert Menzies | National Library of Australia
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