RESUMEN
Podocytes maintain the structure and function of the glomerular filtration barrier. However, podocytes have recently been implicated in the innate immune response, and their function as non-haematopoietic antigen-presenting cells was highlighted. We have shown previously that excessive expression of the chemokine CXCL13 is a distinctive early event for nephritis in a murine model of systemic lupus erythematosus (SLE). Furthermore, we found that CXCL13 is elevated significantly in the serum of patients with SLE-nephritis. In this study, we were able to show for the first time that (i) CXCL13 is expressed locally in glomeruli in a model for SLE-nephritis in mice and that (ii) incubation of human podocytes with CXCL13 induces receptor stimulation of CXCR5 with activation of signalling pathways, resulting in (iii) secretion of proinflammatory cytokines and chemokines in culture supernatant. This cytokine/chemokine cocktail can lead to (iv) a neutrophil respiratory burst in isolated human granulocytes. Taken together, our results provide further evidence that CXCL13 is involved in the pathogenesis of glomerulonephritis and that podocytes can play an active role in local proinflammatory immune responses. Thus, CXCL13 could be a direct target for the therapy of glomerulonephritis in general and for SLE-nephritis in particular.
Asunto(s)
Quimiocina CXCL13/biosíntesis , Glomérulos Renales/metabolismo , Nefritis Lúpica/metabolismo , Animales , Células Cultivadas , Quimiocina CXCL13/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Granulocitos/metabolismo , Humanos , Glomérulos Renales/patología , Lupus Eritematoso Sistémico/metabolismo , Lupus Eritematoso Sistémico/patología , Nefritis Lúpica/patología , Ratones , Neutrófilos/metabolismo , Podocitos/metabolismo , Receptores CXCR5/metabolismoRESUMEN
Renal ischemia-reperfusion (I/R) is associated with activation of the coagulation system and accumulation of blood clotting factors in the kidney. The aim of the present study was to examine the functional impact of fibrinogen on renal inflammation, damage, and repair in the context of I/R injury. In this study, we found that I/R was associated with a significant increase in the renal deposition of circulating fibrinogen. In parallel, I/R stress induced the de novo expression of fibrinogen in tubular epithelial cells, as reflected by RT-PCR, immunofluorescence, and in situ hybridization. In vitro, fibrinogen expression was induced by oncostatin M and hyper-IL-6 in primary tubular epithelial cells, and fibrinogen-containing medium had an inhibitory effect on tubular epithelial cell adhesion and migration. Fibrinogen(+/-) mice showed similar survival as wild-type mice but better preservation in early postischemic renal function. In fibrinogen(-/-) mice, renal function and survival were significantly worse than in fibrinogen(+/-) mice. Renal transplant experiments revealed reduced expression of tubular damage markers and attenuated proinflammatory cytokine expression but increased inflammatory cell infiltrates and transforming growth factor-ß expression in fibrinogen(-/-) isografts. These data point to heterogeneous effects of fibrinogen in renal I/R injury. While a complete lack of fibrinogen may be detrimental, partial reduction of fibrinogen in heterozygous mice can improve renal function and overall outcome.
Asunto(s)
Lesión Renal Aguda/fisiopatología , Fibrinógeno/fisiología , Daño por Reperfusión/fisiopatología , Afibrinogenemia/fisiopatología , Animales , Células Epiteliales/metabolismo , Fibrinógeno/biosíntesis , Fibrinógeno/genética , Interleucina-6/farmacología , Trasplante de Riñón , Masculino , Ratones , Ratones Endogámicos C57BL , Oncostatina M/farmacologíaRESUMEN
After transplantation of solid organs or hematopoietic stem cells, a significant acute decrease in renal function occurs in the majority of patients. Depending on the degree of kidney injury, a large number of patients develop chronic kidney disease (CKD) and some develop end-stage renal disease requiring renal replacement therapy. The incidence varies depending on the transplanted organ, but important risk factors for the development of CKD are preexisting renal disease, hepatitis C, diabetes, hypertension, age, sex, posttransplant acute kidney injury and thrombotic microangiopathy. This review article focuses on the risk factors of posttransplant chronic kidney disease after organ transplantation, considering the current literature and integrates the incidence and the associated mortality rates of acute and chronic kidney disease. Furthermore, we introduce the RECAST (REnal Comorbidity After Solid organ and hematopoietic stem cell Transplantation) registry.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedades Renales/etiología , Trasplante de Órganos/efectos adversos , HumanosRESUMEN
The long-term problems after kidney transplantation have changed considerably in recent years. While formerly immunosuppression and prevention of acute rejection were of prime concern, now attention focuses on chronic alterations of the transplanted organ and long-term survival of the patients. The transplantation procedure itself has evolved into a standardized technique with a high level of surgical quality. Problems involving organ preservation and ischemia/reperfusion damage also play a role, especially in view of chronic aspects. Monitoring of long-term complications should follow a program for the transplanted organ as well as a program for the patient. Monitoring kidney function should address the organ more precisely than has previously been the case. Serum creatinine level and proteinuria alone provide insufficient information and only change long after cellular deterioration has begun. Hence it is imperative that new testing methods be developed. One possibility is offered by protocol biopsies that allow histological and molecular analysis of the kidney at regular intervals. The patient programs concentrate on diagnostics and treatment of the cardiovascular diseases. Furthermore, the patients must be screened for occurrence of neoplasia. There are no prospective studies covering all cardiovascular risk factors after kidney transplantation. This pertains particularly to the subject of hypertension.
Asunto(s)
Oclusión de Injerto Vascular/etiología , Rechazo de Injerto/etiología , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/tendencias , HumanosRESUMEN
BACKGROUND: We explored whether biocompatible dialyzer membranes modulate the inflammatory response during blood contact in patients with systemic inflammation. METHODS: 15 patients with end-stage renal disease and systemic inflammation (mean serum C-reactive protein 86 +/- 4 mg/l) were randomly treated with Cuprophan (CU), polyamide (PA) and vitamin-E coated (VEC) membrane-based dialyzers. RESULTS: Changes in blood pressure, capillary blood oxygen saturation and differential blood counts during the hemodialysis session were not significantly different between the three dialyzers. Baseline blood levels of activated circulating complement (C3a) were more than 100 times above normal, and unlike expected they decreased during hemodialysis treatments (CU: from 7,389 +/- 783 to 5,423 +/- 761 ng/ml; PA: from 7,379 +/- 980 to 5,690 +/- 714 ng/ml; VEC: from 7.377 +/- 714 to 5,360 +/- 1,005 ng/ml; all n.s.). No significant differences between treatments were found with respect to changes in blood concentrations of TNF-alpha, interleukin-6 and interleukin-1 receptor antagonist as well as ICAM-1 (CU: from 451 +/- 41 to 477 +/- 41 ng/ml; PA: from 437 +/- 42 to 449 +/- 40 ng/ml; VEC: from 461 +/- 43 to 460 +/- 47 ng/ml). Furthermore, generation of reactive oxygen species by mononuclear blood cells was comparable during hemodialysis with the CU, PA and VEC dialyzer. CONCLUSION: The choice of dialyzer membrane material does not affect most aspects of biocompatibility when patients have significant systemic inflammation. This confounding variable should be taken into account in studies exploring the effects of biocompatible dialyzer membranes.