C3-glomerulopathy and MGUS: the skin beyond the kidney

C3-glomerulopathy and MGUS: the skin beyond the kidney Learning point for clinicians The diagnosis of C3G is often challenging, as it can mimic other inflammatory diseases. Limited data on the pathogenesis of the disease further complicate its clinical management. Complement deposition is the core pathogenic event in C3G and can be favoured by concomitant paraproteinaemia. Treatments aimed at controlling complement activation directly or through the removal of significant inciting factors, such as monoclonal components, are probably most effective in inducing remission. Introduction C3-glomerulopathy (C3G) is a rare disease characterized by the deposition of C3 within the glomeruli, due to genetically determined or acquired alterations in the deployment of the complement cascade.1 As C3G is usually regarded as a renal-limited disease, little is known about its non-renal manifestations and no evidence for a common pathogenic mechanism has to date been provided. Case description A 70-year-old man with 15-year history of IgGk monoclonal gammopathy of undetermined significance (MGUS) was hospitalized for worsening renal function and critical ischaemia at extremities (ears, nose, upper and lower limbs). His past history included nasal polyposis and occasional nasal crusts since his childhood, left central hypoacusia and motor-sensitive demyelinating polyneuropathy at lower limbs with no evidence of vasculitis or amyloidosis at biopsy. In addition, 4 years earlier he had developed cutaneous leucocytoclastic vasculitis, manifesting as relapsing skin ulcers at lower limbs and purpuric lesions on hands and feet. He had thus been treated with dapsone, azathioprine, intravenous immunoglobulins, cyclophosphamide, cyclosporine and rituximab in combination with high-dose corticosteroids with limited benefit. During the last year, cutaneous manifestations had even worsened following two episodes of severe infection and the patient had undergone amputation of his left index finger. Laboratory tests at admission documented subnephrotic proteinuria, haematuria, low C3 levels and elevated inflammation markers. A search for anti-nuclear, antiphospholipid and anti-neutrophil cytoplasmic antibodies, rheumatoid factor and cryoglobulins resulted negative. Circulating levels of the monoclonal IgGk were stable at 11.4 g/l, with no evidence of Bence-Jones proteinuria. A renal biopsy (Supplementary Figure S1A–C) was consistent with C3G. The patient was treated with 1 g intravenous methylprednisolone for three consecutive days, followed by five cycles of plasma exchange (PEX) and maintained with mofetil mycophenolate 2 g/day. The patient’s renal function and complement levels promptly normalized, in parallel with a reduction of the inflammatory markers and of IgGk monoclonal component titres. The treatment arrested the progression of limb ischaemia, although the patient’s right leg and left forefoot could not be saved. Before surgery, a repeated 5-mm-punch skin biopsy was performed, which documented extensive fibrosis of the reticular derma with a weak vascular C3-positivity. Congo red and immunoglobulin staining at immunofluorescence were negative (Figure 1). Three months after discharge, while on mycophenolate, the patient experienced a relapse of peripheral ischaemia and received further PEX with benefit. Figure 1 View largeDownload slide Histological findings at skin biopsy. Immunofluorescence assay showing the presence of a weak, but predominant C3-positive signal in skin blood vessels. Figure 1 View largeDownload slide Histological findings at skin biopsy. Immunofluorescence assay showing the presence of a weak, but predominant C3-positive signal in skin blood vessels. Discussion Extensive C3 activation and deposition in the glomeruli is the hallmark of C3G.2 Paraproteinaemia might play a role in the pathogenesis of the disease, and clinical evidence suggests that patients with MGUS and C3G have a worse prognosis.2 C3G is usually regarded as a renal-limited disease, although coexisting complement-related diseases such as atypical haemolytic–uraemic syndrome or ocular drusen with partial lipodystrophy have been reported.1 On the other hand, paraproteinaemia can associate with a wide range of inflammatory manifestations at the level of the kidney, the peripheral nervous system or the skin.3,4 Consistently, Chauvet et al.5 recently reported a 6% prevalence of skin involvement in a large cohort of patients with C3G and concomitant MGUS. Here, we have shown that complement-mediated tissue injury might be the shared pathogenic mechanism causing glomerular and extra-glomerular manifestations in patients with C3G and MGUS. Funding None. Supplementary material Supplementary material is available at QJMED online. Conflict of interest: None declared. References 1 Cook HT. C3 glomerulopathy. F1000Research  2017; 6: 248. http://dx.doi.org/10.12688/f1000research.10364.1 Google Scholar CrossRef Search ADS PubMed  2 Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, Traynor C, Flanagan M, Wong L, et al.   C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol  2014; 9: 46– 53. Google Scholar CrossRef Search ADS PubMed  3 Glavey SV, Leung N. Monoclonal gammopathy: the good, the bad and the ugly. Blood Rev  2016; 30: 223– 31. http://dx.doi.org/10.1016/j.blre.2015.12.001 Google Scholar CrossRef Search ADS PubMed  4 Ramirez GA, Campochiaro C, Salmaggi C, Pagliula G, D’Aliberti T, Marcatti M, et al.   Bortezomib in type I cryoglobulinemic vasculitis: are we acting too late? Intern Med  2015; 54: 1119– 23. Google Scholar CrossRef Search ADS PubMed  5 Chauvet S, Fremeaux-Bacchi V, Petitprez F, Karras A, Daniel L, Burtey S, et al.   Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood  2017; 129: 1437– 47. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png QJM: An International Journal of Medicine Oxford University Press

C3-glomerulopathy and MGUS: the skin beyond the kidney

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Oxford University Press
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© The Author(s) 2017. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com
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1460-2725
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1460-2393
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10.1093/qjmed/hcx254
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Abstract

Learning point for clinicians The diagnosis of C3G is often challenging, as it can mimic other inflammatory diseases. Limited data on the pathogenesis of the disease further complicate its clinical management. Complement deposition is the core pathogenic event in C3G and can be favoured by concomitant paraproteinaemia. Treatments aimed at controlling complement activation directly or through the removal of significant inciting factors, such as monoclonal components, are probably most effective in inducing remission. Introduction C3-glomerulopathy (C3G) is a rare disease characterized by the deposition of C3 within the glomeruli, due to genetically determined or acquired alterations in the deployment of the complement cascade.1 As C3G is usually regarded as a renal-limited disease, little is known about its non-renal manifestations and no evidence for a common pathogenic mechanism has to date been provided. Case description A 70-year-old man with 15-year history of IgGk monoclonal gammopathy of undetermined significance (MGUS) was hospitalized for worsening renal function and critical ischaemia at extremities (ears, nose, upper and lower limbs). His past history included nasal polyposis and occasional nasal crusts since his childhood, left central hypoacusia and motor-sensitive demyelinating polyneuropathy at lower limbs with no evidence of vasculitis or amyloidosis at biopsy. In addition, 4 years earlier he had developed cutaneous leucocytoclastic vasculitis, manifesting as relapsing skin ulcers at lower limbs and purpuric lesions on hands and feet. He had thus been treated with dapsone, azathioprine, intravenous immunoglobulins, cyclophosphamide, cyclosporine and rituximab in combination with high-dose corticosteroids with limited benefit. During the last year, cutaneous manifestations had even worsened following two episodes of severe infection and the patient had undergone amputation of his left index finger. Laboratory tests at admission documented subnephrotic proteinuria, haematuria, low C3 levels and elevated inflammation markers. A search for anti-nuclear, antiphospholipid and anti-neutrophil cytoplasmic antibodies, rheumatoid factor and cryoglobulins resulted negative. Circulating levels of the monoclonal IgGk were stable at 11.4 g/l, with no evidence of Bence-Jones proteinuria. A renal biopsy (Supplementary Figure S1A–C) was consistent with C3G. The patient was treated with 1 g intravenous methylprednisolone for three consecutive days, followed by five cycles of plasma exchange (PEX) and maintained with mofetil mycophenolate 2 g/day. The patient’s renal function and complement levels promptly normalized, in parallel with a reduction of the inflammatory markers and of IgGk monoclonal component titres. The treatment arrested the progression of limb ischaemia, although the patient’s right leg and left forefoot could not be saved. Before surgery, a repeated 5-mm-punch skin biopsy was performed, which documented extensive fibrosis of the reticular derma with a weak vascular C3-positivity. Congo red and immunoglobulin staining at immunofluorescence were negative (Figure 1). Three months after discharge, while on mycophenolate, the patient experienced a relapse of peripheral ischaemia and received further PEX with benefit. Figure 1 View largeDownload slide Histological findings at skin biopsy. Immunofluorescence assay showing the presence of a weak, but predominant C3-positive signal in skin blood vessels. Figure 1 View largeDownload slide Histological findings at skin biopsy. Immunofluorescence assay showing the presence of a weak, but predominant C3-positive signal in skin blood vessels. Discussion Extensive C3 activation and deposition in the glomeruli is the hallmark of C3G.2 Paraproteinaemia might play a role in the pathogenesis of the disease, and clinical evidence suggests that patients with MGUS and C3G have a worse prognosis.2 C3G is usually regarded as a renal-limited disease, although coexisting complement-related diseases such as atypical haemolytic–uraemic syndrome or ocular drusen with partial lipodystrophy have been reported.1 On the other hand, paraproteinaemia can associate with a wide range of inflammatory manifestations at the level of the kidney, the peripheral nervous system or the skin.3,4 Consistently, Chauvet et al.5 recently reported a 6% prevalence of skin involvement in a large cohort of patients with C3G and concomitant MGUS. Here, we have shown that complement-mediated tissue injury might be the shared pathogenic mechanism causing glomerular and extra-glomerular manifestations in patients with C3G and MGUS. Funding None. Supplementary material Supplementary material is available at QJMED online. Conflict of interest: None declared. References 1 Cook HT. C3 glomerulopathy. F1000Research  2017; 6: 248. http://dx.doi.org/10.12688/f1000research.10364.1 Google Scholar CrossRef Search ADS PubMed  2 Medjeral-Thomas NR, O’Shaughnessy MM, O’Regan JA, Traynor C, Flanagan M, Wong L, et al.   C3 glomerulopathy: clinicopathologic features and predictors of outcome. Clin J Am Soc Nephrol  2014; 9: 46– 53. Google Scholar CrossRef Search ADS PubMed  3 Glavey SV, Leung N. Monoclonal gammopathy: the good, the bad and the ugly. Blood Rev  2016; 30: 223– 31. http://dx.doi.org/10.1016/j.blre.2015.12.001 Google Scholar CrossRef Search ADS PubMed  4 Ramirez GA, Campochiaro C, Salmaggi C, Pagliula G, D’Aliberti T, Marcatti M, et al.   Bortezomib in type I cryoglobulinemic vasculitis: are we acting too late? Intern Med  2015; 54: 1119– 23. Google Scholar CrossRef Search ADS PubMed  5 Chauvet S, Fremeaux-Bacchi V, Petitprez F, Karras A, Daniel L, Burtey S, et al.   Treatment of B-cell disorder improves renal outcome of patients with monoclonal gammopathy-associated C3 glomerulopathy. Blood  2017; 129: 1437– 47. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2017. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

QJM: An International Journal of MedicineOxford University Press

Published: Mar 1, 2018

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