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Clark D. West - One of the best experts on this subject based on the ideXlab platform.
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nephritic factor and recurrence in the renal transplant of membranoproliferative glomerulonephritis type ii
Pediatric Nephrology, 2008Co-Authors: Clark D. West, John J BisslerAbstract:Animal models suggest a role for nephritic factor in the pathogenesis of glomerular disease, but evidence for a role in human disease is lacking. To assess its role, we applied a recently developed method that allows measurement of low levels of nephritic factor activity to stored serum specimens from three patients who had membranoproliferative glomerulonephritis (MPGN) type II. All three had had renal transplants, and one lost two of three transplants from recurrent disease. Evidence for a role for nephritic factor in human disease was a positive correlation between the level of nephritic factor activity and both the severity of recurrence and an increase in serum creatinine concentration. However, the Hypocomplementemia was never severe; C3 levels of 49–76 mg/dl and nephritic factor levels of 89 U/ml were associated with severe recurrences. We have previously seen severe disease with mild Hypocomplementemia. In contrast, patients with partial lipodystrophy often have severe Hypocomplementemia and, presumably, high levels of nephritic factor yet have a mild glomerulonephritis. Disease severity and nephritic factor levels thus appear to be inversely related. The disease is progressive when only moderate amounts of nephritic factor have been circulating and C3 only mildly depressed.
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composition of nephritic factor ndash generated glomerular deposits in membranoproliferative glomerulonephritis type 2
American Journal of Kidney Diseases, 2001Co-Authors: Clark D. West, David P Witte, James A McadamsAbstract:Abstract Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFs. Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during Hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.
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The alternative pathway C3 convertase and glomerular deposits.
Pediatric Nephrology, 1999Co-Authors: Clark D. West, Andrew J. McadamsAbstract:Five conditions in which the alternative pathway C3 convertase, C3b,Bb, circulates in excess as a result of factor H dysfunction are frequently accompanied by nephritis. These convertase-related nephritides are seen in association with heterozygous absence of a binding site for factor H on C3b (Marder disease), homozygous factor H deficiency, circulating factor H inhibitor, and with the nephritic factors, one of the amplification loop and the other of the terminal pathway, found in membranoproliferative glomerulonephritis (MPGN) types II and III, respectively. Observations which relate convertase to glomerular deposits are: (1) in MPGN type II, subepithelial deposits on the paramesangial segments of the glomerular basement membrane are with high frequency present in patients hypocomplementemic at biopsy, but not in those normocomplementemic; (2) in MPGN type III paramesangial deposits are similarly found with Hypocomplementemia but are present for up to 1 year after normocomplementemia is achieved; (3) in MPGN type III, subendothelial deposits are present only with Hypocomplementemia. The principal deposits foundin factor H deficiency and in Marder disease are also paramesangial. Differences in the incidence, severity, and morphology of the nephritides accompanying convertase in excess may relate to the characteristics of the circulating convertase and/or to the C3 conversion products formed by it.
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membranoproliferative glomerulonephritis type iii association of glomerular deposits with circulating nephritic factor stabilized convertase
American Journal of Kidney Diseases, 1998Co-Authors: Clark D. West, A J McadamsAbstract:Deposits in the glomerular ultrastructure of 44 renal biopsy specimens from 21 patients with membranoproliferative glomerulonephritis (MPGN) type III have been compared with those in the ultrastructure of 34 biopsy specimens from 19 patients with MPGN type I. Previous studies have concluded that subepithelial deposits on the paramesangial portion of the glomerular basement membrane in MPGN types II and III are closely associated with circulating nephritic factor-stabilized convertase. In the present study, subendothelial deposits in MPGN type III were also found to be closely associated with nephritic factor; they were present in 14 of 26 (54%) biopsy specimens obtained during Hypocomplementemia but in none of the 18 biopsy specimens obtained during normocomplementemia (P < 0.001). Subepithelial loop deposits in type III were also more frequent in biopsy specimens obtained during Hypocomplementemia and are probably in some way also associated with circulating stabilized convertase. Taken together, the results of this and previous studies are compatible with the hypothesis that an excess of the C3b-dependent convertase in the circulation is basic to the pathogenesis of MPGN types II and III as well as of several other nephritides associated with factor H dysfunction. The half-life, structural complexity, and size of the convertases circulating in these nephritides increase in the following order: native convertase, convertase stabilized by the nephritic factor of the amplification loop (NFa), and convertase stabilized by nephritic factor of the terminal pathway (NFt). In the same order, the nephritides associated with these convertases more frequently manifest and have increasing amounts of glomerular deposit. This relationship of glomerular deposits with circulating convertase, however, is only circumstantial. There is no evidence that the convertase or a part thereof is a constituent of the deposits. The lesion that is the hallmark of MPGN type III is one in which interruptions of lamina densa are associated with subendothelial and subepithelial deposits, often confluent, and interspersed with multiple layers of new lamina densa-like material. This "type III lesion," which by implication is also associated with circulating nephritic factor, is the most persistent of the glomerular deposits. For reasons that are not yet clear, the type III lesion was absent in three patients who were severely hypocomplementemic, and the diagnosis of type III was made only after this lesion appeared in biopsy specimens obtained later. In MPGN type I, differing from type III, subendothelial deposits were present in 100% of biopsy specimens obtained during Hypocomplementemia and in 47% of those obtained during normocomplementemia. Their persistence in type I may reflect rearrangement and condensation of the deposited material, shown by other investigators to be dependent on the presence of immunoglobulin G, which is largely absent from the deposits in type III. The comparison of deposits in types I and III indicates that relating the presence of subendothelial and paramesangial deposits to the C3 level at the time of biopsy can be helpful in distinguishing types I and III when the type III lesion is not present.
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paramesangial glomerular deposits in membranoproliferative glomerulonephritis type ii correlate with Hypocomplementemia
American Journal of Kidney Diseases, 1995Co-Authors: Clark D. West, James A McadamsAbstract:To gain support for a previously proposed hypothesis that nephritic factors predispose to chronic glomerulonephritis, the glomerular deposits of patients with membranoproliferative glomerulonephritis type II have been studied by electron microscopy and immunofluorescence and the results correlated with the C3 level at the time of biopsy. If, as hypothesized, circulating convertase predisposes to nephritis, finding that the glomeruli of patients hypocomplementemic at biopsy, presumably with nephritic factor-stabilized convertase in their circulation, differ from those of patients normocomplementemic at biopsy would suggest that circulating convertase in some way alters the glomerulus. Among 25 biopsy specimens from 12 patients, Hypocomplementemia did not correlate with capillary loop deposits, but there was strong correlation with deposits in the paramesangial region as detected by electron microscopy. Of 11 patients who were normocomplementemic at biopsy, none had paramesangial deposits in their glomeruli. Of 14 patients who were hypocomplementemic at biopsy, deposits were present in the paramesangium in 12 patients (P < 0.001). The deposits were either on both sides of the paramesangial segment of the basement membrane (waist basement membrane related) or in apposition to the paramesangial basement membrane in a subepithelial position only. The detection of paramesangial deposits in the ultrastructure correlated with the detection of C3-containing mesangial granules by immunofluorescence; immunoglobulin G, C5, properdin, and factor B could not be demonstrated in these granules. The study identifies the mesangial deposits described by others in membranoproliferative glomerulonephritis type II as paramesangial deposits and, more importantly, demonstrates that their presence correlates closely with Hypocomplementemia. It is likely that these deposits in some way result from the presence in the circulation of convertase stabilized by the nephritic factor of the amplification loop.
Pierre Aucouturier - One of the best experts on this subject based on the ideXlab platform.
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immunoglobulin γ3 heavy chain deposition disease report of a case and relationship with Hypocomplementemia
American Journal of Kidney Diseases, 2004Co-Authors: Jun Soma, Hiroshi Sato, Kozo Sato, Tsutomu Sakuma, Hirotaka Saito, Toshinobu Sato, Aicha Abbas, Pierre AucouturierAbstract:Abstract The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and Hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomuruli with the deposition of immunoglobulin γ3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of γ-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of γ-heavy-chain deposition disease (γ-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring γ3-heavy-chain deposition who showed severe Hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with Hypocomplementemia. The authors also discuss here the relationship of HCDD to Hypocomplementemia.
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immunoglobulin γ3 heavy chain deposition disease report of a case and relationship with Hypocomplementemia
American Journal of Kidney Diseases, 2004Co-Authors: Jun Soma, Hiroshi Sato, Kozo Sato, Tsutomu Sakuma, Hirotaka Saito, Toshinobu Sato, Aicha Abbas, Pierre AucouturierAbstract:The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and Hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomeruli with the deposition of immunoglobulin gamma3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of gamma-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of gamma-heavy-chain deposition disease (gamma-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring gamma3-heavy-chain deposition who showed severe Hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with Hypocomplementemia. The authors also discuss here the relationship of HCDD to Hypocomplementemia.
Jun Soma - One of the best experts on this subject based on the ideXlab platform.
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immunoglobulin γ3 heavy chain deposition disease report of a case and relationship with Hypocomplementemia
American Journal of Kidney Diseases, 2004Co-Authors: Jun Soma, Hiroshi Sato, Kozo Sato, Tsutomu Sakuma, Hirotaka Saito, Toshinobu Sato, Aicha Abbas, Pierre AucouturierAbstract:The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and Hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomeruli with the deposition of immunoglobulin gamma3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of gamma-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of gamma-heavy-chain deposition disease (gamma-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring gamma3-heavy-chain deposition who showed severe Hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with Hypocomplementemia. The authors also discuss here the relationship of HCDD to Hypocomplementemia.
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immunoglobulin γ3 heavy chain deposition disease report of a case and relationship with Hypocomplementemia
American Journal of Kidney Diseases, 2004Co-Authors: Jun Soma, Hiroshi Sato, Kozo Sato, Tsutomu Sakuma, Hirotaka Saito, Toshinobu Sato, Aicha Abbas, Pierre AucouturierAbstract:Abstract The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and Hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomuruli with the deposition of immunoglobulin γ3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of γ-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of γ-heavy-chain deposition disease (γ-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring γ3-heavy-chain deposition who showed severe Hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with Hypocomplementemia. The authors also discuss here the relationship of HCDD to Hypocomplementemia.
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successful treatment with steroid pulse therapy in a case of immunotactoid glomerulopathy with Hypocomplementemia
American Journal of Kidney Diseases, 1998Co-Authors: Isao Kurihara, Takao Saito, Hiroshi Sato, Jun Chiba, Jun Saito, Jun Soma, Sadayoshi ItoAbstract:Abstract We report a case of immunotactoid glomerulopathy with severe Hypocomplementemia. The patient was a 47-year-old woman who presented with pitting edema, proteinuria, and hypertension. Serological testings were negative or within normal limits except for Hypocomplementemia. There were no findings of hematopoietic diseases, cryoglobulinemia, and systemic lupus erythematosus. The renal biopsy specimen showed membranoproliferative glomerulonephritis with numerous periodic acid- Schiff (PAS)-positive deposits. Under electron microscopy, however, microtubular structure was shown in the mesangial matrix and the subendothelial and subepithelial spaces of the peripheral capillary loops. These histological features were compatible with those of immunotactoid glomerulopathy. Although conventional oral steroid therapy failed to have an effect on proteinuria and Hypocomplementemia over 3 months, steroid pulse therapy brought dramatic relief: complete remission of proteinuria and normalization of Hypocomplementemia. These findings suggest that intensive immunosuppressive therapy may cure a kind of immunotactoid glomerulopathy with Hypocomplementemia. (Am J Kidney Dis 1998 Jul;32(1):E4)
Hiroshi Sato - One of the best experts on this subject based on the ideXlab platform.
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immunoglobulin γ3 heavy chain deposition disease report of a case and relationship with Hypocomplementemia
American Journal of Kidney Diseases, 2004Co-Authors: Jun Soma, Hiroshi Sato, Kozo Sato, Tsutomu Sakuma, Hirotaka Saito, Toshinobu Sato, Aicha Abbas, Pierre AucouturierAbstract:The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and Hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomeruli with the deposition of immunoglobulin gamma3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of gamma-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of gamma-heavy-chain deposition disease (gamma-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring gamma3-heavy-chain deposition who showed severe Hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with Hypocomplementemia. The authors also discuss here the relationship of HCDD to Hypocomplementemia.
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immunoglobulin γ3 heavy chain deposition disease report of a case and relationship with Hypocomplementemia
American Journal of Kidney Diseases, 2004Co-Authors: Jun Soma, Hiroshi Sato, Kozo Sato, Tsutomu Sakuma, Hirotaka Saito, Toshinobu Sato, Aicha Abbas, Pierre AucouturierAbstract:Abstract The authors describe a 54-year-old woman presenting with proteinuria, hematuria, and Hypocomplementemia whose renal biopsy results showed diffuse increase in mesangial matrix and nodular formations in several glomuruli with the deposition of immunoglobulin γ3-heavy-chain and complement components C1q and C3 in the glomeruli and on the tubular basement membranes, without associated light-chain deposits. Staining for the constant domains of γ-heavy-chain showed a deletion of the first constant domain (CH1). These findings were consistent with those of γ-heavy-chain deposition disease (γ-HCDD). The patient was treated monthly with melphalan and prednisolone although a bone marrow aspirate did not show findings suggestive of plasmacytoma. Six courses of melphalan and prednisolone therapy resulted in a marked reduction of urinary protein excretion and marked rise of complement levels. The current case is the fourth HCDD patient reported featuring γ3-heavy-chain deposition who showed severe Hypocomplementemia and responded to chemotherapy with improved renal parameters and complement levels. A review of previously reported cases of HCDD showed that some but not all HCDD cases were associated with Hypocomplementemia. The authors also discuss here the relationship of HCDD to Hypocomplementemia.
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successful treatment with steroid pulse therapy in a case of immunotactoid glomerulopathy with Hypocomplementemia
American Journal of Kidney Diseases, 1998Co-Authors: Isao Kurihara, Takao Saito, Hiroshi Sato, Jun Chiba, Jun Saito, Jun Soma, Sadayoshi ItoAbstract:Abstract We report a case of immunotactoid glomerulopathy with severe Hypocomplementemia. The patient was a 47-year-old woman who presented with pitting edema, proteinuria, and hypertension. Serological testings were negative or within normal limits except for Hypocomplementemia. There were no findings of hematopoietic diseases, cryoglobulinemia, and systemic lupus erythematosus. The renal biopsy specimen showed membranoproliferative glomerulonephritis with numerous periodic acid- Schiff (PAS)-positive deposits. Under electron microscopy, however, microtubular structure was shown in the mesangial matrix and the subendothelial and subepithelial spaces of the peripheral capillary loops. These histological features were compatible with those of immunotactoid glomerulopathy. Although conventional oral steroid therapy failed to have an effect on proteinuria and Hypocomplementemia over 3 months, steroid pulse therapy brought dramatic relief: complete remission of proteinuria and normalization of Hypocomplementemia. These findings suggest that intensive immunosuppressive therapy may cure a kind of immunotactoid glomerulopathy with Hypocomplementemia. (Am J Kidney Dis 1998 Jul;32(1):E4)
James A Mcadams - One of the best experts on this subject based on the ideXlab platform.
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composition of nephritic factor ndash generated glomerular deposits in membranoproliferative glomerulonephritis type 2
American Journal of Kidney Diseases, 2001Co-Authors: Clark D. West, David P Witte, James A McadamsAbstract:Abstract Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFs. Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during Hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.
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paramesangial glomerular deposits in membranoproliferative glomerulonephritis type ii correlate with Hypocomplementemia
American Journal of Kidney Diseases, 1995Co-Authors: Clark D. West, James A McadamsAbstract:To gain support for a previously proposed hypothesis that nephritic factors predispose to chronic glomerulonephritis, the glomerular deposits of patients with membranoproliferative glomerulonephritis type II have been studied by electron microscopy and immunofluorescence and the results correlated with the C3 level at the time of biopsy. If, as hypothesized, circulating convertase predisposes to nephritis, finding that the glomeruli of patients hypocomplementemic at biopsy, presumably with nephritic factor-stabilized convertase in their circulation, differ from those of patients normocomplementemic at biopsy would suggest that circulating convertase in some way alters the glomerulus. Among 25 biopsy specimens from 12 patients, Hypocomplementemia did not correlate with capillary loop deposits, but there was strong correlation with deposits in the paramesangial region as detected by electron microscopy. Of 11 patients who were normocomplementemic at biopsy, none had paramesangial deposits in their glomeruli. Of 14 patients who were hypocomplementemic at biopsy, deposits were present in the paramesangium in 12 patients (P < 0.001). The deposits were either on both sides of the paramesangial segment of the basement membrane (waist basement membrane related) or in apposition to the paramesangial basement membrane in a subepithelial position only. The detection of paramesangial deposits in the ultrastructure correlated with the detection of C3-containing mesangial granules by immunofluorescence; immunoglobulin G, C5, properdin, and factor B could not be demonstrated in these granules. The study identifies the mesangial deposits described by others in membranoproliferative glomerulonephritis type II as paramesangial deposits and, more importantly, demonstrates that their presence correlates closely with Hypocomplementemia. It is likely that these deposits in some way result from the presence in the circulation of convertase stabilized by the nephritic factor of the amplification loop.