RESUMEN
BACKGROUND: Plasma cell dyscrasias (PCD) are characterized by an abnormal production of intact monoclonal immunoglobulins or parts such as heavy or light chains. In most cases, the monoclonal protein (also termed paraprotein) is produced by a clonal plasma cell population. The production of monoclonal proteins can result in deposits of various types and localization depending on the type, amount, and electrochemical properties of the paraprotein. One histopathologic presentation, albeit rare, are crystalline deposits. They can form in various organs and hence cause a wide spectrum of symptoms. CASE PRESENTATION: A 49-year-old man presented to the emergency department with eyestrain and foreign body sensation after overhead drilling. Examination of the eyes revealed crystalline deposits in the cornea of both eyes. After additional diagnostic testing, deposits were attributed to free light chains. Monoclonal gammopathy of undetermined significance (MGUS) was diagnosed according to serum electrophoresis and immunofixation. Four years later, new onset of proteinuria was detected. A percutaneous biopsy of the kidney showed severe light chain podocytopathy with secondary focal segmental glomerulosclerosis (FSGS) and light chain proximal tubulopathy (LCPT). In these lesions, crystalline deposits identical to the corneal deposits were found in ultrastructural and immunofluorescent analysis. The patient was diagnosed with monoclonal gammopathy of renal significance (MGRS), and a plasma cell directed therapy was initiated. CONCLUSIONS: PCD can present with a wide array of symptoms and are notoriously difficult to diagnose. Extrarenal manifestations such as crystalline deposits in the cornea are one possible manifestation. The case presented herein emphasizes the notion that extrarenal paraprotein deposits warrant a thorough search for the underlying clonal disease.
Asunto(s)
Córnea/patología , Riñón/patología , Paraproteinemias/diagnóstico , Biopsia , Errores Diagnósticos , Humanos , Masculino , Persona de Mediana Edad , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Paraproteinemias/complicacionesRESUMEN
Detachment or apoptosis of podocytes leads to proteinuria and glomerulosclerosis. There are no current interventions for diabetic or non-diabetic glomerular diseases specifically preventing podocyte apoptosis. Binding of erythropoiesis stimulating proteins (ESPs) to receptors on non-hematopoietic cells has been shown to have anti-apoptotic effects in vitro, in vivo, and in preliminary human studies. Recently, erythropoietin receptors were identified on podocytes; therefore, we tested effects of darbepoetin alfa in preventing podocyte apoptosis. Cultured immortalized mouse podocytes were treated with low-dose ultraviolet-C (uv-C) irradiation to induce apoptosis in the absence or presence of darbepoetin alfa. Apoptosis was quantified by Hoechst staining and by caspase 3 cleavage assessed by Western blots. Pretreatment with darbepoetin alfa significantly reduced podocyte apoptosis with this effect involving intact Janus family protein kinase-2 (JAK2) and AKT signaling pathways. Additionally, darbepoetin alfa was found protective against transforming growth factor-beta1 but not puromycin aminonucleoside induced apoptosis. Mice with anti-glomerular antibody induced glomerulonephritis had significantly less proteinuria, glomerulosclerosis, and podocyte apoptosis when treated with darbepoetin alfa. Our studies show that treatment of progressive renal diseases characterized by podocyte apoptosis with ESPs may be beneficial in slowing progression of chronic kidney disease.
Asunto(s)
Apoptosis/efectos de los fármacos , Eritropoyetina/análogos & derivados , Glomerulonefritis/prevención & control , Podocitos/efectos de los fármacos , Sustancias Protectoras/farmacología , Transducción de Señal/efectos de los fármacos , Animales , Anticuerpos , Apoptosis/efectos de la radiación , Autoanticuerpos , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Darbepoetina alfa , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Eritropoyetina/farmacología , Eritropoyetina/uso terapéutico , Glomerulonefritis/complicaciones , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Glomeruloesclerosis Focal y Segmentaria/etiología , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/prevención & control , Janus Quinasa 2/metabolismo , Ratones , Podocitos/metabolismo , Podocitos/patología , Podocitos/efectos de la radiación , Sustancias Protectoras/uso terapéutico , Proteinuria/etiología , Proteinuria/patología , Proteinuria/prevención & control , Proteínas Proto-Oncogénicas c-akt/metabolismo , Puromicina Aminonucleósido/farmacología , Receptores de Eritropoyetina/efectos de los fármacos , Receptores de Eritropoyetina/metabolismo , Transducción de Señal/efectos de la radiación , Factor de Crecimiento Transformador beta1/metabolismo , Rayos UltravioletaRESUMEN
Micro-vascular and renal complications in diabetic patients are a considerable clinical challenge. In a previous study, we found a significant decrease in vascular endothelial growth factor A (VEGF-A) mRNA levels in glomeruli from patients with diabetic nephropathy (DN). We now set out to investigate the relationship between reduced VEGF-A and connective tissue growth factor (CTGF) expression levels, the number of podocytes, and the extent of interstitial fibrosis. Laser capture microdissection was applied to obtain glomerular RNA from 28 patients with DN and 22 controls. mRNA levels of VEGF-A, CTGF, nephrin, podocin, and Wilms tumor1 (WT1) were measured using real-time polymerase chain reaction. Protein expression was evaluated using immuno-stainings for VEGF-A and CTGF, as well as markers for podocytes (WT1) and endothelial cells (CD31). We found a significant decrease in glomerular mRNA levels for VEGF-A (2.5 times), CTGF (1.6), nephrin (2.8), podocin (3.3), and WT1 (1.7) in patients with DN. There was a significant correlation between expression of podocyte markers and VEGF-A mRNA levels, and an inverse correlation between podocin message and the extent of interstitial fibrosis. CD31-positive area was significantly decreased (3.2 times) in patients with DN. Reduction of angiogenic factors correlated with the extent of interstitial fibrosis. This downregulation was related to a reduction of podocytes in DN. The results may suggest that downregulation of VEGF-A and CTGF in DN is a result of podocyte loss.
Asunto(s)
Nefropatías Diabéticas/inmunología , Proteínas Inmediatas-Precoces/biosíntesis , Péptidos y Proteínas de Señalización Intercelular/biosíntesis , Podocitos , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Adulto , Anciano , Factor de Crecimiento del Tejido Conjuntivo , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Although a beneficial effect of hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, i.e. statins, on cell-mediated immunity has been suggested in vivo and in vitro, little is known about the molecular and biochemical events by which statins inhibit T cell proliferation. To address this question, we investigated the effects of atorvastatin (AT) on intracellular cytokine production, T cell activation markers, cell cycle progression and apoptosis in human CD4(+) T cells. AT did not influence intracellular cytokine production after short-term stimulation of whole blood with phorbol myristate acetate (PMA)/ionomycin or superantigen (SEB). In contrast, AT influenced CD45RA to RO switching dose-dependently, as well as CD25 expression, and caused cell cycle arrest in the G1 phase after long-term T cell stimulation. This occurred in conjunction with a reduced expression of cyclin-dependent kinases 2 and 4 and p21(wav1/cip1) and was paralleled by an increased protein expression of p27(kip1). In addition to G1 arrest, increased apoptosis was observed in AT-treated cells. In line with this, the expression of Bcl-xl and pBad were decreased by AT. Apoptosis was independent of caspases 3 and 9 activation. The inhibitory effect of AT on T cell proliferation could be overcome by addition of mevalonic acid or geranylgeranyl pyrophosphate, but not by farnesyl pyrophosphate or squalen, suggesting reduced protein prenylation. Activation of Rho, Rac and Ras were strongly reduced in AT-treated T cells, suggesting that impaired geranylation of these molecules might underlie the inhibitory effect of AT on T cell proliferation.
Asunto(s)
Linfocitos T CD4-Positivos/efectos de los fármacos , Ácidos Heptanoicos/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Activación de Linfocitos/efectos de los fármacos , Proteínas de Unión al GTP Monoméricas/antagonistas & inhibidores , Pirroles/farmacología , Apoptosis/efectos de los fármacos , Atorvastatina , Western Blotting , Linfocitos T CD4-Positivos/inmunología , Caspasas/fisiología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Citocinas/biosíntesis , Relación Dosis-Respuesta Inmunológica , Activación Enzimática/efectos de los fármacos , Humanos , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Activación de Linfocitos/inmunologíaRESUMEN
Treatment of organ donors with catecholamines reduces acute rejection episodes and improves long-term graft survival after renal transplantation. The aim of this study was to investigate the effect of catecholamine pre-treatment on ischemia/reperfusion (I/R)- and cold preservation injury in rat kidneys. I/R-injury was induced by clamping the left kidney vessels for 60 min along with a contralateral nephrectomy. Cold preservation injury was induced by storage of the kidneys for 24 h at +4 degrees Celsius in University of Wisconsin solution, followed by syngeneic transplantation. Rats were pre-treated with either dopamine (DA), dobutamine (DB), or norepinephrine (2, 5, and 10 microg/kg/min, each group) intravenously via an osmotic minipump for 24 h before I/R- and cold preservation injury. Pre-treatment with DA (2 or 5 microg/kg/min) and DB (5 microg/kg/min) improved recovery of renal function after I/R-injury and dose dependently reduced mononuclear and major histocompatibility complex class II-positive cells infiltrating the kidney after I/R-injury. One day after I/R-injury, upregulation of transforming growth factor (TGF)-beta 1 and 2 and phosphorylation of p42/p44 mitogen-activated protein kinases was observed in kidneys of animals treated with DA or DB. DA (5 microg/kg/min) and DB (5 microg/kg/min) pre-treatment reduced endothelial cell damage after 24 h of cold preservation. Only DA pre-treatment improved renal function and reduced renal inflammation after 24 h of cold preservation and syngeneic transplantation. Our results demonstrate a protective effect of pre-treatment with catecholamines on renal inflammation and function after I/R- or cold preservation injury. This could help to explain the potent organoprotective effects of catecholamine pre-treatment observed in human kidney transplantation.
Asunto(s)
Catecolaminas/farmacología , Criopreservación/métodos , Precondicionamiento Isquémico/métodos , Trasplante de Riñón , Daño por Reperfusión/tratamiento farmacológico , Animales , Frío , Dobutamina/farmacología , Dopamina/farmacología , Dopaminérgicos/farmacología , Supervivencia de Injerto , Riñón/efectos de los fármacos , Riñón/fisiología , Riñón/cirugía , Masculino , Nefrectomía/métodos , Norepinefrina/farmacología , Ratas , Ratas Endogámicas Lew , Daño por Reperfusión/prevención & control , Simpatomiméticos/farmacologíaRESUMEN
Interindividual differences of endothelial cells in response to endotoxins might contribute to the diversity in clinical outcome among septic patients. The present study was conducted to test the hypothesis that endothelial cells (EC) with high and low proinflammatory potential exist and to dissect the molecular basis underlying this phenomenon. Thirty human umbilical vein endothelial cell (HUVEC) lines were stimulated for 24 h with lipopolysaccharide (LPS) and screened for interleukin (IL)-8 production. Based on IL-8 production five low and five high producers, tentatively called types I and II responders, respectively, were selected for genome-wide gene expression profiling. From the 74 genes that were modulated by LPS in all type II responders, 33 genes were not influenced in type I responders. Among the 41 genes that were increased in both responders, 17 were expressed significantly stronger in type II responders. Apart from IL-8, significant differences in the expression of proinflammatory related genes between types I and II responders were found for adhesion molecules [intercellular adhesion molecule (ICAM-1), E-selectin)], chemokines [monocyte chemoattractant protein (MCP-1), granulocyte chemotactic protein (GCP-2)], cytokines (IL-6) and the transcription factor CCAAT/enhancer binding protein-delta (C/EBP-delta). Type I responders also displayed a low response towards tumour necrosis factor (TNF)-alpha. In general, maximal activation of nuclear factor (NF)-kappaB was achieved in type I responders at higher concentrations of LPS compared to type II responders. In the present study we demonstrate that LPS-mediated gene expression differs quantitatively and qualitatively in types I and II responders. Our results suggest a pivotal role for common transcription factors as a low inflammatory response was also observed after TNF-alpha stimulation. Further studies are required to elucidate the relevance of these findings in terms of clinical outcome in septic patients.
Asunto(s)
Endotelio Vascular/inmunología , Interleucina-8/biosíntesis , Lipopolisacáridos/inmunología , Factores de Transcripción/inmunología , Células Cultivadas , Quimiocinas/biosíntesis , Ensayo de Cambio de Movilidad Electroforética/métodos , Células Endoteliales/inmunología , Perfilación de la Expresión Génica/métodos , Regulación de la Expresión Génica/inmunología , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-8/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Sepsis/inmunología , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
In vitro and in vivo studies have demonstrated that apart from its hemodynamic action dopamine can modulate immune responses. Dopamine reduces the synthesis of proinflammatory and induces the synthesis of anti-inflammatory mediators. Dopamine inhibits neurohormone synthesis, lymphocyte proliferation and platelet aggregation. It reduces the phagocytic activity of neutrophils and induces apoptosis. Particularly with regard to sepsis, where high serum dopamine levels are reached by enhanced endogenous production, exogenous application and impaired clearance, this immunomodulation may have a clinical impact. This review summarizes dopamine-mediated immunomodulating effects to advance the knowledge regarding dopamine as an immune regulator under septic conditions.
Asunto(s)
Formación de Anticuerpos/fisiología , Cardiotónicos/uso terapéutico , Dopamina/uso terapéutico , Inmunidad Celular/fisiología , Factores Inmunológicos , Sepsis/tratamiento farmacológico , Sepsis/inmunología , Animales , Cardiotónicos/farmacología , Proliferación Celular/efectos de los fármacos , Dopamina/farmacología , Hemodinámica/efectos de los fármacos , Humanos , Mediadores de Inflamación , Linfocitos/efectos de los fármacos , Neurotransmisores/biosíntesis , Fagocitosis/efectos de los fármacosRESUMEN
While most of our understanding of immune dysfunction in dialysis patients involves alterations in CD28-CD80/86 signalling, nothing is known of CD46-mediated co-stimulation of T cells in these patients. Because C3b/C4b bind to CD46 and complement activation occurs during haemodialysis (HD), we addressed whether CD46-mediated T cell activation is altered in HD (n = 9), peritoneal dialysis (PD) (n = 10) and predialysis patients (n = 8) compared to healthy controls (HC) (n = 8). T cell surface markers, T cell proliferation and interleukin (IL)-10 production were studied in CD4(+)T cells. In addition, CD46 splice-variants and IL-10 promoter gene polymorphisms were studied by reverse transcription (RT) or amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), respectively. In all uraemic patients, irrespective of the stage of renal insufficiency or dialysis modality, a significant increase in the percentage of CD25 positivity in naive CD4(+)T cells was found (64% +/- 21%versus 23% +/- 18%, P < 0.001). Lymphocytes of HD patients proliferated in greater numbers and produced more IL-10 after co-stimulation with anti-CD46 than after co-stimulation with anti-CD28. This was also found in CD4(+)T cells of PD patients, albeit to a lesser extent. In contrast, with T cells of predialysis patients and of HC, co-stimulation via CD28 was more efficient. The observed alterations in T cell proliferation and IL-10 production were associated neither with CD46 splice variants nor with IL-10 promoter gene polymorphisms. Lymphocytes of HD patients show an increased response on CD46 co-stimulation. These data suggest that ongoing complement activation in HD patients may lead to alterations in acquired immunity.