Aggregation of γG3 proteins: relevance to the hyperviscosity syndrome

Capra, J D; Kunkel, Henry G.

doi:10.1172/jci106272

Cited by 119 publications

(45 citation statements)

References 28 publications

(24 reference statements)

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“…In all four patients with PGNMID reported here, the IgG subtype deposited in glomeruli was IgG3, which is the isoform identified in most native kidney biopsies of PGNMID (6,13). This subtype, which comprises only 8% of IgG in the serum of normal individuals, has the unique physicochemical property of self-aggregability via Fc-Fc interactions (18,19). In addition, compared with other IgG subtypes, it has the highest molecular weight, the greatest complement-fixing ability, and the most positive charge, properties that may make it intrinsically "nephritogenic" (18,19).…”

Section: Discussionmentioning

confidence: 74%

“…This subtype, which comprises only 8% of IgG in the serum of normal individuals, has the unique physicochemical property of self-aggregability via Fc-Fc interactions (18,19). In addition, compared with other IgG subtypes, it has the highest molecular weight, the greatest complement-fixing ability, and the most positive charge, properties that may make it intrinsically "nephritogenic" (18,19). None of our patients had an identifiable serum monoclonal protein by conventional immunochemical analysis (i.e., serum protein electrophoresis and immunofixation), which is in agreement with our prior finding in the native kidney that a demonstrable circulating paraprotein is more common in patients with monoclonal IgG1 or IgG2 deposits (6).…”

Section: Discussionmentioning

confidence: 99%

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Proliferative Glomerulonephritis with Monoclonal IgG Deposits Recurs in the Allograft

Nasr

Sethi²,

Cornell³

et al. 2011

Clinical Journal of the American Society of Nephrology

124

118

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SummaryBackground and objectives Proliferative GN with monoclonal IgG deposits (PGNMID) is a newly described entity resembling immune complex GN. Its potential to recur in the allograft is undefined.Design, setting, participants, & measurements The first cases of recurrent PGNMID in the allograft are reported. ResultsThe cohort includes four Caucasians (3 women, 1 man) with a mean age 58.5 years. No patient had M spike or hematologic malignancy. Recurrence was first documented by biopsy at a mean of 3.8 months posttransplant for indications of renal insufficiency in four patients, proteinuria in three patients, and microhematuria in three patients. Monoclonal IgG deposits (3 IgG3 and 1 IgG3) in the transplants had identical heavy-and light-chain isotypes as in the native kidneys. In two patients, a pattern of endocapillary GN was identified in the native and transplant biopsies, whereas two patients with membranoproliferative GN in the native kidney developed endocapillary or mesangial GN in the transplant. Recurrence was treated with combined high-dose prednisone plus rituximab (n ϭ 3) or plus cyclophosphamide (n ϭ 1). After a mean posttransplant follow-up of 43 months, all four patients achieved reduction in proteinuria and three had reduction in creatinine. Repeat biopsies showed reduced histologic activity after treatment.Conclusions PGNMID can recur in the transplant despite the absence of a serum M spike. Recurrence is heralded by proteinuria, hematuria, and allograft dysfunction and manifests diverse histologic patterns. Although the pathogenesis remains unknown, early immunosuppressive therapy appears to stabilize the course.

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Section: Discussionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Proliferative Glomerulonephritis with Monoclonal IgG Deposits Recurs in the Allograft

Nasr

Sethi²,

Cornell³

et al. 2011

Clinical Journal of the American Society of Nephrology

124

118

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“…Of the four subclasses, IgG3, which composes only 8% of IgG in the circulation, has several properties that allow it to be intrinsically "nephritogenic." 19,20 (1) It is the most positively charged subclass (pI 8.2 to 9.0), favoring affinity for intrinsic anionic sites in the GCW. (2) It has the highest molecular weight (170,000 Da), making it more size-restricted by the glomerular filtration barrier.…”

Section: Discussionmentioning

confidence: 99%

Proliferative Glomerulonephritis with Monoclonal IgG Deposits

Nasr

Satoskar

Markowitz

et al. 2009

Journal of the American Society of Nephrology

349

434

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Dysproteinemias that result in monoclonal glomerular deposits of IgG are relatively uncommon. Here, we report the largest series of proliferative glomerulonephritis with monoclonal IgG deposits, a form of renal involvement by monoclonal gammopathy that mimics immune-complex glomerulonephritis. We retrospectively identified 37 patients, most of whom were white (81%), female (62%), or older than 50 yr (65%). At presentation, 49% had nephrotic syndrome, 68% had renal insufficiency, and 77% had hematuria. In 30% of the patients, we identified a monoclonal serum protein with the same heavy-and light-chain isotypes as the glomerular deposits (mostly IgG1 or IgG2), but only one patient had myeloma. Histologic patterns were predominantly membranoproliferative (57%) or endocapillary proliferative (35%) with membranous features. Electron microscopy revealed granular, nonorganized deposits, and immunofluorescence demonstrated glomerular deposits that stained for a single light-chain isotype and a single heavy-chain subtype, most commonly IgG3 (53%). During an average of 30.3 mo of follow-up for 32 patients with available data, 38% had complete or partial recovery, 38% had persistent renal dysfunction, and 22% progressed to ESRD. Correlates of ESRD on univariate analysis were higher creatinine at biopsy, percentage of glomerulosclerosis, and degree of interstitial fibrosis but not immunomodulatory treatment or presence of a monoclonal spike. On multivariate analysis, higher percentage of glomerulosclerosis was the only independent predictor of ESRD. Only one patient lacking a monoclonal spike at presentation subsequently developed a monoclonal spike and no patient with a monoclonal spike at presentation subsequently developed a hematologic malignancy. We conclude that proliferative glomerulonephritis with monoclonal IgG deposits does not seem to be a precursor of myeloma in the vast majority of patients.

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“…It should be mentioned that human IgG3 have physicochemical properties similar to those of murine IgG3. All the human IgG3 myeloma proteins studied undergo a concentration-and temperature-dependent aggregation, though not always cryoprecipitation [28][29][30][31]. Although this aggregating site is apparently localized in the Fd fragment of the human IgG3 heavy (H) chain [29], it remains to de determined whether this is also the case for murine IgG3.…”

Section: Introductionmentioning

confidence: 99%