RESUMEN
Introduction: The immunomodulatory properties of mesenchymal stromal cells (MSC) have been well-characterized in in-vitro and in-vivo models. We have previously shown that liver MSC (L-MSC) are superior inhibitors of T-cell activation/proliferation, NK cell cytolytic function, and macrophage activation compared to adipose (A-MSC) and bone marrow MSC (BM-MSC) in-vitro. Method: To test these observations in-vivo, we infused these types of MSC into mice with unilateral renal artery stenosis (RAS), an established model of kidney inflammation. Unilateral RAS was induced via laparotomy in 11-week-old, male 129-S1 mice under general anesthesia. Control mice had sham operations. Human L-MSC, AMSC, and BM-MSC (5x105 cells each) or PBS vehicle were injected intra-arterially 2 weeks after surgery. Kidney morphology was studied 2 weeks after infusion using micro-MRI imaging. Renal inflammation, apoptosis, fibrosis, and MSC retention were studied ex-vivo utilizing western blot, immunofluorescence, and immunohistological analyses. Results: The stenotic kidney volume was smaller in all RAS mice, confirming significant injury, and was improved by infusion of all MSC types. All MSC-infused groups had lower levels of plasma renin and proteinuria compared to untreated RAS. Serum creatinine improved in micetreated with BM- and L-MSC. All types of MSC located to and were retained within the stenotic kidneys, but L-MSC retention was significantly higher than A- and BM-MSC. While all groups of MSC-treated mice displayed reduced overall inflammation and macrophage counts, L-MSC showed superior potency in-vivo at localizing to the site of inflammation and inducing M2 (reparative) macrophage polarization to reduce inflammatory changes. Discussion: These in-vivo findings extend our in-vitro studies and suggest that L-MSC possess unique anti-inflammatory properties that may play a role in liver-induced tolerance and lend further support to their use as therapeutic agents for diseases with underlying inflammatory pathophysiology.
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Isquemia , Hígado , Macrófagos , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Animales , Ratones , Trasplante de Células Madre Mesenquimatosas/métodos , Masculino , Humanos , Hígado/patología , Hígado/inmunología , Isquemia/terapia , Isquemia/inmunología , Macrófagos/inmunología , Modelos Animales de Enfermedad , Inflamación/inmunología , Inflamación/terapia , Activación de Macrófagos , Obstrucción de la Arteria Renal/terapia , Obstrucción de la Arteria Renal/inmunología , Riñón/patología , Riñón/inmunologíaRESUMEN
Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells-derived extracellular vesicles (EVs). The anti-inflammatory TGF-ß (transforming growth factor-ß) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-ß expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8+ T cells were detected in stenotic kidneys treated with Lean-EVs compared with MetS-EVs, and renal vein levels of interleukin-1ß were reduced. In vitro, coculture of Lean-EVs with activated T cells led to greater TGF-ß-dependent regulatory T cells induction than did MetS-EVs. Therefore, the beneficial effects of mesenchymal stem cells-derived EVs on injured kidneys might be partly mediated by their content of TGF-ß signaling components, which permitting increased Treg preponderance. Modulating EV cargo and transforming their functionality might be useful for renal repair.
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Vesículas Extracelulares , Síndrome Metabólico/complicaciones , Obstrucción de la Arteria Renal/complicaciones , Insuficiencia Renal Crónica/terapia , Linfocitos T Reguladores/inmunología , Animales , Técnicas de Cocultivo , Citocinas/sangre , Carbohidratos de la Dieta/toxicidad , Grasas de la Dieta/toxicidad , Vesículas Extracelulares/química , Femenino , Inflamación , Infusiones Intraarteriales , Síndrome Metabólico/sangre , MicroARNs/análisis , MicroARNs/farmacología , Monocitos/citología , Monocitos/inmunología , Distribución Aleatoria , Arteria Renal , Obstrucción de la Arteria Renal/sangre , Obstrucción de la Arteria Renal/inmunología , Circulación Renal , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/inmunología , Transducción de Señal/efectos de los fármacos , Porcinos , Linfocitos T Reguladores/citología , Factor de Crecimiento Transformador beta/antagonistas & inhibidoresRESUMEN
The antiphospholipid syndrome is a common autoimmune disease caused by pathogenic antiphospholipid antibodies, leading to recurrent thrombosis and/or obstetrical complications. Importantly for nephrologists, antiphospholipid antibodies are associated with various renal manifestations including large renal vessel thrombosis, renal artery stenosis, and a constellation of intrarenal lesions that has been termed antiphospholipid nephropathy. This last condition associates various degrees of acute thrombotic microangiopathy, proliferative and fibrotic lesions of the intrarenal vessels, and ischemic modifications of the renal parenchyma. The course of the disease can range from indolent nephropathy to devastating acute renal failure. The pejorative impact of antiphospholipid antibody-related renal complication is well established in the context of systemic lupus erythematous or after renal transplantation. In contrast, the exact significance of isolated antiphospholipid nephropathy remains uncertain. The evidence to guide management of the renal complications of antiphospholipid syndrome is limited. However, the recent recognition of the heterogeneous molecular mechanisms underlying the progression of intrarenal vascular lesions in antiphospholipid syndrome have opened promising tracks for patient monitoring and targeted therapeutic intervention.
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Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/complicaciones , Enfermedades Renales/inmunología , Enfermedades Renales/terapia , Obstrucción de la Arteria Renal/inmunología , Trombosis/inmunología , Aloinjertos/irrigación sanguínea , Aloinjertos/inmunología , Aloinjertos/patología , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/terapia , Progresión de la Enfermedad , Humanos , Hipertensión/etiología , Inmunosupresores/uso terapéutico , Riñón/irrigación sanguínea , Riñón/inmunología , Riñón/patología , Enfermedades Renales/diagnóstico , Trasplante de Riñón/efectos adversos , Imagen por Resonancia Magnética , Intercambio Plasmático , Obstrucción de la Arteria Renal/complicaciones , Obstrucción de la Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/tratamiento farmacológico , Trombosis/diagnóstico por imagen , Trombosis/tratamiento farmacológico , Trombosis/epidemiología , beta 2 Glicoproteína I/inmunologíaRESUMEN
Recent studies have shown that inflammation plays a critical role in the initiation and progression of hypertensive kidney disease, including renal artery stenosis. However, the signaling mechanisms underlying the induction of inflammation are poorly understood. We found that CXCL16 was induced in the kidney in a murine model of renal artery stenosis. To determine whether CXCL16 is involved in renal injury and fibrosis, wild-type and CXCL16 knockout mice were subjected to renal artery stenosis induced by placing a cuff on the left renal artery. Wild-type and CXCL16 knockout mice had comparable blood pressure at baseline. Renal artery stenosis caused an increase in blood pressure that was similar between wild-type and CXCL16 knockout mice. CXCL16 knockout mice were protected from RAS-induced renal injury and fibrosis. CXCL16 deficiency suppressed bone marrow-derived fibroblast accumulation and myofibroblast formation in the stenotic kidneys, which was associated with less expression of extracellular matrix proteins. Furthermore, CXCL16 deficiency inhibited infiltration of F4/80(+) macrophages and CD3(+) T cells in the stenotic kidneys compared with those of wild-type mice. Taken together, our results indicate that CXCL16 plays a pivotal role in the pathogenesis of renal artery stenosis-induced renal injury and fibrosis through regulation of bone marrow-derived fibroblast accumulation and macrophage and T-cell infiltration.
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Lesión Renal Aguda/genética , Quimiocina CXCL6/genética , Fibroblastos , Riñón/patología , Macrófagos/inmunología , Obstrucción de la Arteria Renal/genética , Linfocitos T/inmunología , Lesión Renal Aguda/inmunología , Animales , Presión Sanguínea , Western Blotting , Células de la Médula Ósea , Quimiocina CXCL16 , Quimiocina CXCL6/inmunología , Modelos Animales de Enfermedad , Fibrosis/genética , Fibrosis/inmunología , Técnica del Anticuerpo Fluorescente , Frecuencia Cardíaca , Hipertensión/complicaciones , Hipertensión/inmunología , Riñón/inmunología , Riñón/metabolismo , Masculino , Ratones , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Obstrucción de la Arteria Renal/inmunología , Insuficiencia Renal Crónica/etiología , Insuficiencia Renal Crónica/inmunología , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Renal artery stenosis is the main cause of renovascular hypertension and results in ischemic nephropathy characterized by inflammation, oxidative stress, microvascular loss, and fibrosis with consequent functional failure. Considering the limited number of strategies that effectively control renovascular hypertension and restore renal function, we propose that cell therapy may be a promising option based on the regenerative and immunosuppressive properties of stem cells. This review addresses the effects of mesenchymal stem cells (MSC) in an experimental animal model of renovascular hypertension known as 2 kidney-1 clip (2K-1C). Significant benefits of MSC treatment have been observed on blood pressure and renal structure of the stenotic kidney. The mechanisms involved are discussed.
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Hipertensión Renovascular/cirugía , Riñón , Trasplante de Células Madre Mesenquimatosas , Obstrucción de la Arteria Renal/cirugía , Animales , Enfermedad Crónica , Modelos Animales de Enfermedad , Humanos , Hipertensión Renovascular/inmunología , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/patología , Hipertensión Renovascular/fisiopatología , Riñón/inmunología , Riñón/metabolismo , Riñón/patología , Riñón/fisiopatología , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo , Comunicación Paracrina , Recuperación de la Función , Regeneración , Obstrucción de la Arteria Renal/inmunología , Obstrucción de la Arteria Renal/metabolismo , Obstrucción de la Arteria Renal/patología , Obstrucción de la Arteria Renal/fisiopatología , Transducción de SeñalRESUMEN
In this study, we analyze the outcomes of transplant renal artery stenosis (TRAS), determine the different anatomical positions of TRAS, and establish cardiovascular and immunological risk factors associated with its development. One hundred thirty-seven of 999 (13.7%) patients had TRAS diagnosed by angiography; 119/137 (86.9%) were treated with angioplasty, of which 113/137 (82.5%) were stented. Allograft survival in the TRAS+ intervention, TRAS+ nonintervention and TRAS- groups was 80.4%, 71.3% and 83.1%, respectively. There was no difference in allograft survival between the TRAS+ intervention and TRAS- groups, p = 0.12; there was a difference in allograft survival between the TRAS- and TRAS+ nonintervention groups, p < 0.001, and between the TRAS+ intervention and TRAS+ nonintervention groups, p = 0.037. TRAS developed at the anastomosis, within a bend/kink or distally. Anastomotic TRAS developed in living donor recipients; postanastomotic TRAS (TRAS-P) developed in diabetic and older patients who received grafts from deceased, older donors. Compared with the TRAS- group, patients with TRAS-P were more likely to have had rejection with arteritis, odds ratio (OR): 4.83 (1.47-15.87), p = 0.0095, and capillaritis, OR: 3.03 (1.10-8.36), p = 0.033. Patients with TRAS-P were more likely to have developed de novo class II DSA compared with TRAS- patients hazard ratio: 4.41 (2.0-9.73), p < 0.001. TRAS is a heterogeneous condition with TRAS-P having both alloimmune and traditional cardiovascular risk factors.
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Anticuerpos/análisis , Antígenos de Histocompatibilidad Clase II/inmunología , Trasplante de Riñón/efectos adversos , Obstrucción de la Arteria Renal/inmunología , Donantes de Tejidos , Adulto , Anciano , Angiografía de Substracción Digital/efectos adversos , Femenino , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Masculino , Persona de Mediana Edad , Obstrucción de la Arteria Renal/diagnóstico , Obstrucción de la Arteria Renal/cirugía , Factores de Riesgo , Stents , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVES: Atherosclerotic renal artery stenosis (ARAS) reduces renal blood flow and is a potential cause of chronic kidney injury, yet little is known regarding inflammatory pathways in this disorder in human participants. This study aimed to examine the hypothesis that reduced renal blood flow (RBF) in ARAS would be associated with tissue TGF-ß activation and inflammatory cell accumulation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This cross-sectional study of ARAS of varying severity compared transjugular biopsy specimens in patients with ARAS (n=12, recruited between 2008 and 2012) with tissue from healthy kidney donors (n=15) and nephrectomy specimens from individuals with total vascular occlusion (n=65). ARAS patients were studied under controlled conditions to measure RBF by multidetector computed tomography and tissue oxygenation by blood oxygen level-dependent magnetic resonance imaging. RESULTS: Compared with the nonstenotic contralateral kidneys, RBF was reduced in poststenotic kidneys (242±149 versus 365+174 ml/min; P<0.01) as was single-kidney GFR (28±17 versus 41±19 ml/min; P<0.01), whereas cortical and medullary oxygenation were relatively preserved. Tissue TGF-ß immunoreactivity was higher in ARAS patients compared with those with both normal kidneys and those with total occlusion (mean score 2.4±0.7 versus 1.5+1.1 in the nephrectomy group and versus 0±0 in donors; P<0.01). By contrast, the number of CD68+ macrophages was higher with greater disease severity (from 2.2±2.7 in normal to 22.4±18 cells/high-power field in nephrectomy samples; P<0.001). CONCLUSIONS: The results of this study indicate robust stimulation of TGF-ß associated with macrophage infiltration within the human kidney with vascular occlusive disease.
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Aterosclerosis/inmunología , Macrófagos/inmunología , Obstrucción de la Arteria Renal/inmunología , Factor de Crecimiento Transformador beta/inmunología , Anciano , Aterosclerosis/patología , Aterosclerosis/cirugía , Biopsia , Femenino , Fibrosis , Humanos , Trasplante de Riñón , Macrófagos/citología , Masculino , Persona de Mediana Edad , Nefrectomía , Nefritis Intersticial/inmunología , Nefritis Intersticial/patología , Nefritis Intersticial/cirugía , Obstrucción de la Arteria Renal/patología , Obstrucción de la Arteria Renal/cirugía , Circulación Renal/inmunología , Insuficiencia Renal Crónica/inmunología , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/cirugía , Donantes de Tejidos , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
BACKGROUND: The selection of patients with renal artery stenosis (RAS) likely to improve glomerular filtration rate (GFR) after percutaneous transluminal renal angioplasty is difficult. We examined basal hemodynamic and inflammatory factors linked to improved stenotic kidney (STK) function after percutaneous transluminal renal angioplasty in swine RAS. METHODS AND RESULTS: Fifteen pigs after 6 weeks of hemodynamically significant RAS were studied before and 4 weeks after technically successful percutaneous transluminal renal angioplasty+stenting. STK and contralateral kidney hemodynamics and function were evaluated by multidetector computed-tomography before and after acetylcholine challenge. Single-kidney deoxyhemoglobin (R2*, reciprocal to blood relaxation) and energy-dependent tubular function were assessed using blood-oxygen-level-dependent magnetic resonance imaging before and after furosemide. Baseline renal vein and inferior vena cava levels of inflammatory markers were measured and their gradient and net release calculated. Baseline parameters were compared with normal (n=7) and sham-RAS (n=7) pigs and correlated with the change in STK-GFR after revascularization (ΔGFR). Four weeks after percutaneous transluminal, renal angioplasty blood pressure was normalized in all animals, but STK-GFR improved in 10 of 15 (ΔGFR =+22.0±8.5 mL/min). ΔGFR correlated inversely with basal STK-GFR, renal release of inflammatory markers, and medullary R2* response to furosemide, but directly with GFR response to acetylcholine. Basal contralateral kidney GFR correlated directly with ΔGFR. CONCLUSIONS: Low basal STK-GFR with preserved response to acetylcholine may predict benefit from revascularization in RAS, whereas renal inflammation and robust STK-R2* responses to furosemide (possibly reflecting avid tubular oxygen consumption) are associated with less favorable outcomes. These tools may be useful for identification of patients likely to improve renal function after revascularization.
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Angioplastia de Balón , Tasa de Filtración Glomerular , Hemodinámica , Riñón/irrigación sanguínea , Riñón/fisiopatología , Microcirculación , Microvasos/fisiopatología , Nefritis/prevención & control , Obstrucción de la Arteria Renal/terapia , Circulación Renal , Acetilcolina/farmacología , Angioplastia de Balón/efectos adversos , Angioplastia de Balón/instrumentación , Animales , Biomarcadores/sangre , Modelos Animales de Enfermedad , Femenino , Furosemida/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Hemodinámica/efectos de los fármacos , Mediadores de Inflamación/sangre , Riñón/diagnóstico por imagen , Riñón/efectos de los fármacos , Imagen por Resonancia Magnética , Microcirculación/efectos de los fármacos , Nefritis/sangre , Nefritis/diagnóstico , Nefritis/inmunología , Nefritis/fisiopatología , Arteria Renal/fisiopatología , Obstrucción de la Arteria Renal/sangre , Obstrucción de la Arteria Renal/diagnóstico , Obstrucción de la Arteria Renal/inmunología , Obstrucción de la Arteria Renal/fisiopatología , Circulación Renal/efectos de los fármacos , Venas Renales/fisiopatología , Stents , Sus scrofa , Factores de Tiempo , Tomografía Computarizada por Rayos XRESUMEN
UNLABELLED: Renal artery stenosis (RAS) causes renovascular hypertension and renal damage, which may result from tissue inflammation. We have previously shown that the kidney in RAS exhibits increased expression of monocyte chemoattractant protein (MCP)-1, but its contribution to renal injury remained unknown. This study tested the hypothesis that MCP-1 contributes to renal injury and dysfunction in the stenotic kidney. METHODS: Kidney hemodynamics, function, and endothelial function were quantified in pigs after 10 weeks of experimental RAS (n = 7), RAS supplemented with the MCP-1 inhibitor bindarit (RAS + bindarit, 50 mg/kg/day orally, n = 6), and normal controls (n = 8). Renal inflammation was assessed by the immunoreactivity of MCP-1, its receptor chemotactic cytokine receptor 2, and NFkappaB, and oxidative stress by nicotinamide adenine dinucleotide phosphate-oxidase expression and in-situ superoxide production. Renal microvascular density was evaluated by micro-CT and fibrosis by trichrome staining, collagen-I immunostaining, and hydroxyproline content. RESULTS: After 10 weeks of RAS, blood pressure was similarly elevated in RAS and RAS + bindarit. Compared with normal controls, stenotic RAS kidneys had decreased renal blood flow (5.4 +/- 1.6 vs. 11.4 +/- 1.0 ml/min/kg, P < 0.05) and glomerular filtration rate and impaired endothelial function, which were significantly improved in bindarit-treated RAS pigs (to 8.4 +/- 0.8 ml/min/kg, P < 0.05 vs. RAS). Furthermore, bindarit markedly decreased tubulointerstitial (but not vascular) oxidative stress, inflammation, and fibrosis, and slightly increased renal microvascular density. The impaired renovascular endothelial function, increased oxidative-stress, and fibrosis in the contralateral kidney were also improved by bindarit. CONCLUSION: MCP-1 contributes to functional and structural impairment in the kidney in RAS, mainly in the tubulointerstitial compartment. Its inhibition confers renoprotective effects by blunting renal inflammation and thereby preserving the kidney in chronic RAS.
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Quimiocina CCL2/metabolismo , Hipertensión Renovascular/metabolismo , Hipertensión Renovascular/fisiopatología , Obstrucción de la Arteria Renal/metabolismo , Obstrucción de la Arteria Renal/fisiopatología , Circulación Renal/fisiología , Animales , Quimiocina CCL2/antagonistas & inhibidores , Quimiocina CCL2/inmunología , Modelos Animales de Enfermedad , Fibrosis , Hipertensión Renovascular/inmunología , Indazoles/farmacología , Túbulos Renales/metabolismo , Túbulos Renales/patología , NADPH Oxidasas/metabolismo , FN-kappa B/metabolismo , Nefritis/inmunología , Nefritis/metabolismo , Nefritis/fisiopatología , Propionatos/farmacología , Receptores CCR2/metabolismo , Obstrucción de la Arteria Renal/inmunología , Sus scrofa , Regulación hacia Arriba/fisiología , Urotelio/metabolismoRESUMEN
PURPOSE: Time changes in plasma concentrations of six different cytokines were investigated to evaluate the inflammatory response to renal artery stent placement. MATERIALS AND METHODS: A total of 22 patients (17 men; mean age, 66 years +/- 13) with ostial renal artery stenosis and poorly controlled hypertension treated with stent placement were studied. Blood samples were collected at baseline and at 24 hours and 6 months after the intervention. Plasma concentrations of (i) tumor necrosis factor-alpha, (ii) interleukin-6 (IL-6), (iii) monocyte chemoattractant protein-1, (iv) intercellular adhesion molecule-1, (v) vascular cell adhesion molecule-1, and (vi) regulated upon activatin normal T-cell expressed presumed secreted were measured. Restenosis diagnosed with imaging follow-up at 6 months was recorded. Plasma concentrations of the aforementioned cytokines were compared between patients with and without restenosis. RESULTS: IL-6 concentration increased significantly 24 hours after stent placement (8.3 pg/mL +/- 1.24 vs. 2.76 pg/mL +/- 1.27 at baseline) and returned to baseline levels (2.6 pg/mL +/- 1.77) at 6-month follow-up (P < .0001). No significant changes occurred in the concentrations of any other cytokines at the three time points. Baseline and 6-month concentrations of IL-6 were significantly higher in patients with restenosis than in those without restenosis (8.13 pg/mL +/- 4 vs 0.75 pg/mL +/- 0.47 [P < .005] and 9.55 pg/mL +/- 6.5 vs 0.42 pg/mL +/- 0.35 [P < .02], respectively). CONCLUSIONS: Renal artery angioplasty with stent placement induces an inflammatory response, as evidenced by increased IL-6 production. Additionally, IL-6 seems to identify patients prone to develop restenosis; therefore, it might be used as an early predictor of restenosis after renal angioplasty with stent placement. However, larger studies are required to confirm IL-6 as a potential predictor of restenosis.
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Prótesis Vascular/efectos adversos , Citocinas/sangre , Oclusión de Injerto Vascular/etiología , Oclusión de Injerto Vascular/inmunología , Inflamación/etiología , Inflamación/inmunología , Obstrucción de la Arteria Renal/inmunología , Obstrucción de la Arteria Renal/cirugía , Stents/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Angioplastia/efectos adversos , Angioplastia/instrumentación , Angioplastia/métodos , Biomarcadores/sangre , Femenino , Oclusión de Injerto Vascular/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The diagnosis of antiphospholipid syndrome (APS) relies on clinical and laboratory criteria, which have been recently outlined in specific consensus conferences. Renal involvement in APS is not infrequent and includes different clinical patterns. For clinical purposes a distinction can be made between large vessel and microvascular involvement. Renal artery stenosis is frequent in APS. In case of microvascular involvement with an acute clinical course a differential diagnosis with other thrombotic microangiopathic diseases has to be made, taking in account thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, malignant hypertension, drug nephrotoxicity (cyclosporin) and others. The disease is often chronic, with hypertension, different degrees of renal insufficiency and mild proteinuria. In patients with systemic lupus erythematosus and antiphospholipid antibodies the prognosis of kidney disease is generally poorer than in lupus alone. Finally, the kidney is almost invariably a target in catastrophic antiphospholipid syndrome. Anticoagulation is the therapy of choice, especially in arterial stenosis and acute disease, but is probably also indicated in chronic and subacute patterns. The role of immunomodulatory therapy has to be assessed.
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Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/complicaciones , Factores Inmunológicos/sangre , Enfermedades Renales/inmunología , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/inmunología , Diagnóstico Diferencial , Quimioterapia Combinada , Humanos , Hipertensión/inmunología , Inmunosupresores/uso terapéutico , Enfermedades Renales/diagnóstico , Enfermedades Renales/tratamiento farmacológico , Obstrucción de la Arteria Renal/inmunologíaRESUMEN
OBJECTIVES: To study the relationship between antiphospholipid antibodies and kidney diseases. METHODS: We reviewed the medical literature from 1968 to 2005 using MEDLINE and the keywords antiphospholipid syndrome, anticardiolipin antibodies, lupus anticoagulant, hypertension, renal artery stenosis, renal vascular thrombosis, thrombotic microangiopathy, and glomerulonephritis. RESULTS: The renal manifestations of the antiphospholipid syndrome may result from thrombosis occurring at any location within the renal vasculature, that is, in the renal artery trunk or branches, intraparenchymal arteries and arterioles, glomerular capillaries, and the renal veins. The spectrum of these manifestations includes renal artery stenosis and/or malignant hypertension, renal infarction, renal vein thrombosis, thrombotic microangiopathy, increased allograft vascular thrombosis, and reduced survival of renal allografts. More recently nonthrombotic conditions like glomerulonephritis have also been reported. CONCLUSION: The kidney appears to be a major target organ in both primary and secondary APS. Early detection of renal involvement may improve the prognosis of these patients.
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Síndrome Antifosfolípido/complicaciones , Hipertensión/inmunología , Enfermedades Renales/inmunología , Enfermedades Vasculares/inmunología , Anticuerpos Antifosfolípidos/sangre , Humanos , Hipertensión/sangre , Hipertensión/etiología , Enfermedades Renales/sangre , Enfermedades Renales/etiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/inmunología , Nefritis Lúpica/sangre , Nefritis Lúpica/etiología , Nefritis Lúpica/inmunología , Obstrucción de la Arteria Renal/sangre , Obstrucción de la Arteria Renal/etiología , Obstrucción de la Arteria Renal/inmunología , Enfermedades Vasculares/sangre , Enfermedades Vasculares/etiologíaRESUMEN
Renal thrombotic manifestations have been reported since the earliest descriptions of the antiphospholipid (Hughes) syndrome (APS). The spectrum of clinical features associated with antiphospholipid nephropathy continues to widen. This review will highlight recent developments such as the prevalence of hypertension, livedo reticularis and renal artery stenosis as well as the ultrastructural changes seen in antiphospholipid nephropathy. The increasing risks of renal transplantation in antiphospholipid antibody positive patients is also discussed leading some authors to question whether these patients should undergo transplantation at all.
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Síndrome Antifosfolípido/inmunología , Enfermedades Renales/inmunología , Riñón/irrigación sanguínea , Síndrome Antifosfolípido/complicaciones , Humanos , Hipertensión , Enfermedades Renales/cirugía , Trasplante de Riñón , Obstrucción de la Arteria Renal/inmunología , Síndrome de SneddonAsunto(s)
Infecciones por Chlamydophila/inmunología , Chlamydophila pneumoniae/inmunología , Enfermedad de la Arteria Coronaria , Hipertensión Renovascular , Obstrucción de la Arteria Renal , Anticuerpos Antibacterianos/sangre , Enfermedad de la Arteria Coronaria/inmunología , Enfermedad de la Arteria Coronaria/microbiología , Humanos , Hipertensión Renovascular/inmunología , Hipertensión Renovascular/microbiología , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Obstrucción de la Arteria Renal/inmunología , Obstrucción de la Arteria Renal/microbiologíaRESUMEN
Heat shock proteins (Hsp) are families of phylogenetically conserved molecules that have a range of cytoprotective and intracellular functional roles. Reactivity to heat shock proteins has been implicated in the development of autoimmune disease and tissue expression of heat shock proteins and increased levels of anti-Hsp antibodies have also been reported in vascular disease. This study compared circulating levels of Hsp60 and Hsp70 and antihuman Hsp60, antihuman Hsp70, and antimycobacterial Hsp65 antibodies in peripheral (PVD) and renal (RVD) vascular disease with those in age- and sex-matched controls. Levels of Hsp70 were higher in both PVD (median 580 vs 40; P < 0.01) and RVD (median 160 vs 0; P < 0.03), whereas there were no differences in Hsp60 levels. Anti-Hsp60 antibody levels were elevated in PVD (146 vs 81 arbitrary units/ml; P < 0.04), but not RVD. This is the first study to demonstrate increased levels of circulating Hsp70 in pathological disease states; however, its physiological role remains to be determined.
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Proteínas HSP70 de Choque Térmico/sangre , Enfermedades Vasculares Periféricas/sangre , Obstrucción de la Arteria Renal/sangre , Anciano , Anciano de 80 o más Años , Autoanticuerpos/análisis , Chaperonina 60/sangre , Chaperonina 60/inmunología , Interpretación Estadística de Datos , Femenino , Proteínas HSP70 de Choque Térmico/inmunología , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Enfermedades Vasculares Periféricas/inmunología , Obstrucción de la Arteria Renal/inmunologíaRESUMEN
We identified the cell surface glycoprotein Thy-1 on the endothelium of newly formed blood vessels in four models of angiogenesis in adult rats. Anti-Thy-1 staining showed that Thy-1 was upregulated in adventitial blood vessels after balloon injury to the carotid artery. Preabsorption with a rat Thy-1-Ig fusion construct eliminated all immunoreactivity and thus confirmed the specificity of the Thy-1 staining. Thy-1 was also expressed in the endothelium of small blood vessels formed after tumor implantation in the cornea, in periureteral vessels formed after ligation of the renal artery, and in small blood vessels of the uterus formed during pregnancy. In contrast with its expression during adult angiogenesis, Thy-1 was not expressed in the endothelium of blood vessels during embryonic angiogenesis. In vitro, the inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha upregulated Thy-1 mRNA by 8- and 14-fold, respectively. Vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-beta, and platelet-derived growth factor-BB had no effect on Thy-1 mRNA. Thus, Thy-1 appears to be a marker of adult but not embryonic angiogenesis. The upregulation of Thy-1 by cytokines but not growth factors indicates the importance of inflammation in the pathogenesis of adult angiogenesis.
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Traumatismos de las Arterias Carótidas , Córnea/irrigación sanguínea , Citocinas/farmacología , Endotelio Vascular/fisiopatología , Regulación de la Expresión Génica , Glioblastoma/irrigación sanguínea , Neovascularización Patológica , Neovascularización Fisiológica , Obstrucción de la Arteria Renal/fisiopatología , Antígenos Thy-1/biosíntesis , Angioplastia de Balón , Animales , Biomarcadores , Arterias Carótidas/inmunología , Arterias Carótidas/patología , Córnea/inmunología , Córnea/patología , Desarrollo Embrionario y Fetal , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Glioblastoma/inmunología , Inmunohistoquímica , Inflamación , Interleucina-1/farmacología , Masculino , Embarazo , Ratas , Ratas Sprague-Dawley , Obstrucción de la Arteria Renal/inmunología , Antígenos Thy-1/análisis , Transcripción Genética/efectos de los fármacos , Transcripción Genética/inmunología , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de von Willebrand/análisis , Factor de von Willebrand/biosíntesisRESUMEN
Transplant renal artery stenosis (TRAS) is a common complication after transplantation and is an important cause of graft dysfunction. Damage from graft rejection, trauma, and atherosclerosis have been implicated as possible causes. We reviewed all 917 patients transplanted in our unit since 1978 to study the prevalence, clinical features, and possible causes of TRAS. Seventy-seven patients with TRAS were identified. The detected incidence was 2.4% before the introduction of color doppler ultrasonography (CDU) and rose to 12.4% after CDU was introduced in 1985, giving an overall incidence of 8.4% during a mean follow-up period of 6.9 years. The TRAS group was compared with a control group of 77 transplanted patients matched for age, year of transplant, sex, and number of previous grafts. Mean ages for the study and control groups were 43.6 +/- 15 and 44.8 +/- 13.7 yr. A total of 25% of cases of TRAS were diagnosed within the first 8 wk of transplantation and in 60% within the first 30 wk (median = 23 wk). All patients were treated with angioplasty, 28 patients had recurrence of TRAS requiring multiple angioplasties (maximum 5) and 1 went on to have surgery. Angioplasty resulted in a significant fall in plasma creatinine. Patient and graft survival were significantly worse in the TRAS group: 69% vs. 83% (P < 0.05) and 56% vs. 74% (P < 0.05) (TRAS vs. Control), respectively. There was a significantly higher incidence of rejection, especially cellular rejection in the TRAS group, 0.67 vs. 0.35 episodes per patient (P < 0.01) (TRAS vs. Control). Recurrence but not occurrence of TRAS was associated with the use of cyclosporine.
Asunto(s)
Trasplante de Riñón/efectos adversos , Obstrucción de la Arteria Renal/etiología , Adulto , Femenino , Supervivencia de Injerto , Antígenos HLA/inmunología , Prueba de Histocompatibilidad , Humanos , Trasplante de Riñón/inmunología , Masculino , Persona de Mediana Edad , Obstrucción de la Arteria Renal/diagnóstico por imagen , Obstrucción de la Arteria Renal/inmunología , Ultrasonografía Doppler en ColorRESUMEN
Although unilateral clamping of the renal artery to induce chronic ischemia of the kidney tissue has been utilized in several animal species, the resultant morphologic, ultrastructural and immunologic changes have never been well characterized. Moreover, the pathogenesis of these changes, as well as their roles in causing or facilitating the development of chronic tubulointerstitial nephritis have not been known. To examine some of these issues, male Sprague-Dawley rats were subjected to unilateral stenosis of the left main renal artery for 28 days. Stenotic and contralateral kidneys of experimental animals and kidneys from sham-operated controls were subjected to: (1) light microscopic, electron microscopic and immunofluorescent studies; (2) morphometric quantitation of the structural changes; (3) staining for actin, epithelial membrane antigen, keratin, and vimentin by immunoperoxidase technique; (4) staining for complex glycoproteins by a panel of 13 lectins; and (5) phenotyping and quantitation of the interstitial inflammatory infiltrates by monoclonal antibodies, using immunoperoxidase technique. The results reveal that: (1) The ischemic kidney tissue displays marked tubulointerstitial damages including abundant interstitial chronic inflammatory infiltrates, with good preservation of glomerular structure, which is consistent with the standard criteria of chronic tubulointerstitial nephritis. (2) The antigenic profile of the ischemic tubular epithelium displayed marked alterations including a neo-expression of vimentin and keratin, as well as a loss of endogenous avidin binding activity, Ia antigen and several complex surface glycoproteins detectable by lectins. (3) Neither electron dense deposits nor immunoglobulins are detectable in the kidneys from experimental or control animals. (4) Tubulitis, defined as infiltration of tubular epithelium by inflammatory cells, was present in up to 42.2% of tubular cross sections of the ischemic kidneys. (5) The interstitial inflammatory infiltrates were composed of B lymphocytes, T helper lymphocytes, and macrophages whereas the T non-helper lymphocytes were scanty, a phenotypic pattern similar to that of several other experimental rat models of chronic tubulointerstitial nephritis. It is concluded that: (1) In the Sprague-Dawley rats, ischemia alone can cause a constellation of changes fulfilling the accepted features of chronic interstitial nephritis; (2) ischemia alters the antigenic profile of the tubular epithelium and thereby may initiate a cell mediated immune response, accounting for the observed tubulitis and interstitial inflammation; and (3) ischemia may well be the final common pathway for chronic tubulointerstitial nephritis of diverse etiologies.