RESUMEN
There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin is demonstrated. Recently, proliferative GN with monoclonal immunoglobulin deposits (PGNMID) has incorporated a light chain variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of C3 is found in addition to monotypic light chain, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year-old man who presented with nephrotic syndrome and was found to have κ light chain multiple myeloma. Immune staining of the glomerulus was positive only for κ light chain and C3, with the striking appearance of nonamyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for light chain and complement and consider local mechanisms whereby monoclonal κ light chain fibrils may have triggered AP activation within the glomerulus.
Asunto(s)
Complemento C3/metabolismo , Glomerulonefritis Membranoproliferativa/diagnóstico , Inmunoglobulina G/inmunología , Glomérulos Renales/ultraestructura , Adulto , Biopsia , Fibrosis/diagnóstico , Fibrosis/inmunología , Fibrosis/metabolismo , Glomerulonefritis Membranoproliferativa/inmunología , Glomerulonefritis Membranoproliferativa/metabolismo , Humanos , Inmunoglobulina G/metabolismo , Glomérulos Renales/metabolismo , Masculino , Microscopía ElectrónicaRESUMEN
BACKGROUND: Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection. CASE PRESENTATION: We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years' follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren's syndrome in three cases. CONCLUSION: Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.
Asunto(s)
Crioglobulinemia/complicaciones , Crioglobulinas , Glomerulonefritis/complicaciones , Inmunoglobulina M/sangre , Cadenas kappa de Inmunoglobulina/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Síndrome de Sjögren/complicaciones , Anciano , Crioglobulinemia/sangre , Crioglobulinemia/terapia , Ciclofosfamida/uso terapéutico , Femenino , Glomerulonefritis/terapia , Glucocorticoides/uso terapéutico , Humanos , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/terapia , Intercambio Plasmático , Rituximab/uso terapéuticoRESUMEN
Antiphospholipid syndrome (APS) may occur in isolation or in association with systemic lupus erythematosus (SLE), with the potential to cause renal failure via several distinct pathologies. Renal transplantation in the presence of APS carries a risk of early graft loss from arterial or venous thrombosis, or thrombotic microangiopathy (TMA). Whilst perioperative anticoagulation reduces the risk of large vessel thrombosis, it may result in significant haemorrhage, and its efficacy in preventing post-transplant TMA is uncertain. Here, we report a patient with end-stage kidney disease (ESKD) due to lupus nephritis and APS, in whom allograft TMA developed soon after transplantation despite partial anticoagulation. TMA resolved with plasma exchange-based therapy albeit with some irreversible graft damage and renal impairment. We discuss the differential diagnosis of post-transplant TMA, and current treatment options.
Asunto(s)
Síndrome Antifosfolípido/complicaciones , Fallo Renal Crónico/cirugía , Trasplante de Riñón/efectos adversos , Nefritis Lúpica/complicaciones , Microangiopatías Trombóticas/etiología , Adulto , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/diagnóstico , Síndrome Antifosfolípido/tratamiento farmacológico , Biopsia , Diagnóstico Diferencial , Humanos , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/etiología , Nefritis Lúpica/diagnóstico , Masculino , Intercambio Plasmático , Valor Predictivo de las Pruebas , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/terapia , Resultado del TratamientoAsunto(s)
Papulosis Atrófica Maligna/diagnóstico , Tromboangitis Obliterante/diagnóstico , Adulto , Arterias/patología , Diagnóstico Diferencial , Humanos , Riñón/patología , Pierna/patología , Masculino , Papulosis Atrófica Maligna/patología , Tromboangitis Obliterante/patología , Trombosis/patologíaRESUMEN
Despite its prevalence, the molecular basis of squamous cell carcinoma (SCC) remains poorly understood. Here, we identify the developmental transcription factor Grhl3 as a potent tumor suppressor of SCC in mice, and demonstrate that targeting of Grhl3 by a miR-21-dependent proto-oncogenic network underpins SCC in humans. Deletion of Grhl3 in adult epidermis evokes loss of expression of PTEN, a direct GRHL3 target, resulting in aggressive SCC induced by activation of PI3K/AKT/mTOR signaling. Restoration of Pten expression completely abrogates SCC formation. Reduced levels of GRHL3 and PTEN are evident in human skin, and head and neck SCC, associated with increased expression of miR-21, which targets both tumor suppressors. Our data define the GRHL3-PTEN axis as a critical tumor suppressor pathway in SCC.