The role of lymphatics in renal inflammation

Progressive renal diseases are characterized by tubulointerstitial inflammatory cell recruitment, tubular atrophy and fibrosis. Various aspects of the recruitment of leukocytes have been extensively studied, but the exit routes (i.e. the lymphatic vessels and their biology) have only recently found attention. Similar to the recruitment of inflammatory cells, the exit is coordinated by an orchestrated interaction of chemotactic cytokines and adhesion molecules. During inflammatory injury, new routes are created by the de novo formation of lymphatic vessels, i.e. neolymphangiogenesis. These newly formed lymphatic vessels help to cope with the increase in interstitial fluid related to inflammation. Here, we review some aspects of lymphatic biology and the current knowledge about lymphatic vessels in renal inflammatio

Sichere Shuntchirurgie - aus der Sicht des Nephrologen

Hintergrund: Aufgrund des zunehmenden Alters und der Komorbiditäten der Dialysepatienten haben sich die Voraussetzungen für Dialysezugänge und für eine sichere Shuntchirurgie verändert. Fragestellung: Welchen Beitrag leistet der Nephrologe zur Sicherheit der Versorgung von Patienten mit chronischer Niereninsuffizienz mit Dialysezugängen? Material und Methodik: Erfahrungsbericht und Literaturübersicht von Nephrologen, eingebettet in ein interdisziplinäres Team für Gefäßzugänge. Ergebnisse: Eine wesentliche Komponente für eine sichere Shuntchirurgie ist die zeitgerechte Planung und Anlage des optimalen Gefäßzugangs. Der Patient steht hier im Zentrum und entscheidet die Art der Dialyse. Dem interdisziplinären Team an behandelnden Ärzten (Hausarzt, Nephrologe, Angiologe, interventioneller Radiologe, Gefäßchirurg) kommt die Aufgabe einer zeitgerechten Planung und Durchführung des Eingriffs zu. Schließlich muss die Reifung des Shunts postoperativ überwacht werden. Schlussfolgerung: Für die Sicherheit des Patienten ist sowohl die Entscheidung für den richtigen Zugang als auch der richtige Zeitpunkt von Bedeutung. Um den Trend der häufigen Nutzung von Kathetern entgegen zu wirken, ist zukünftig eine noch frühere Planung notwendig. Background: The population of patients in need of renal replacement therapy has changed with an increase in age and a rising number of comorbidities. Therefore, the prerequisites for a vascular access for hemodialysis have become less favorable and the risk for the patient has increased. Objective: What is the role of the nephrologist for a safe access placement in patients with chronic renal insufficiency? Material and methods: A literature search was carried out and descriptions of experiences of nephrologists working in an interdisciplinary vascular access team were included. Results: Nephrologists play a pivotal role in the timely patient education and planning of an optimal vascular access. The decision of the patient defines the type of dialysis to be used. The nephrologist together with the interdisciplinary vascular access team (general practitioner, angiologist, interventional radiologist and vascular surgeon) decides on the best access, depending on the clinical needs, clinical examination and duplex sonography mapping. Timely planning of access creation and surveillance after surgery are important tasks for the nephrologist. Conclusion: For the safety of the patient the decision for the best access and correct timing are of pivotal importance. To reduce the number of catheters it will probably be necessary to start with the planning of a vascular access earlier in the future

Hyperglycemia and Hyperlipidemia Act Synergistically to Induce Renal Disease in LDL Receptor-Deficient BALB Mice

Diabetic nephropathy is the leading cause of end-stage renal disease in Western countries, but only a portion of diabetic patients develop diabetic nephropathy. Dyslipidemia represents an important aspect of the metabolic imbalance in diabetic patients. In this study, we addressed the impact of combined hyperlipidemia and hyperglycemia on renal pathology. Kidneys from wildtype (WT) or LDL receptor-deficient BALB/cBy mice (BALB. LDLR -/-) were examined at 22 weeks of age. Diabetes was induced by administration of streptozotocin and mice were randomly assigned to either standard chow or Western diet. Chow fed BALB. LDLR -/- mice did not demonstrate renal abnormalities, whereas BALB. LDLR -/- mice fed a Western diet showed occasional glomerular and tubulointerstitial foam cells. Diabetic WT mice had modestly increased glomerular cellularity and extracellular matrix. Hyperlipidemic and diabetic BALB. LDLR -/- mice exhibited an increase in glomerular cellularity and extracellular matrix, accumulation of glomerular and tubulointerstitial foam cells and mesangial lipid deposits. The tubular epithelium demonstrated pronounced lipid induced tubular degeneration with increased tubular epithelial cell turnover. Hyperlipidemia and hyperglycemia seem to act synergistically in inducing renal injury in the BALB. LDLR-/- mouse. This model of diabetic nephropathy is unique in its development of tubular lesions and may represent a good model for hyperlipidemia-exacerbated diabetic nephropathy. Copyright (C) 2004 S. Karger AG, Basel

Synergistic Bcl-2 inhibition by ABT-737 and cyclosporine A

Survival of lymphocytes and melanocyte stem cells critically depends on B cell lymphoma 2 (Bcl-2). In T lymphocytes, a basal calcineurin activity maintains Bcl-2 expression in naïve cells, and the activation of the calcineurin pathway orchestrates the regulation of the intrinsic apoptosis pathway after antigen recognition. Therefore, calcineurin inhibitors might potentiate the pro-apoptotic effect of pharmacological Bcl-2 inhibitors on lymphatic cells. In vitro, a reduced Bcl-2 expression in lymphocytes exposed to calcineurin inhibitors increased their sensitivity to the small molecule Bcl-2 inhibitor ABT-737. This correlated with an augmented pro-apoptotic activity of ABT-737 on lymphocytes in combination with cyclosporine A in naïve mice in vivo. Interestingly, similar processes were observed in melanocytes. ABT-737 induced a fur depigmentation at the site of injection, and this effect was expanded to a generalized depigmentation in combination with cyclosporine A. Thus, inhibiting calcineurin increases the pro-apoptotic potency of ABT-737 in cells depending on Bcl-2 for survival. The increased efficacy of Bcl-2 inhibitors in combination with cyclosporine A might be relevant to exploit their anti-neoplastic and immuno-modulatory propertie

Expression of the chemokine receptor CCR6 in human renal inflammation

Background. Nodular inflammatory cell infiltrates with defined microarchitecture, i.e. tertiary lymphoid organs, develop in the tubulointerstitium during chronic renal inflammation. CCR6 and the corresponding ligand CCL20 are involved in the formation of gut-associated lymphatic tissue. We hypothesized that CCR6 might be involved in the formation of nodular infiltrates in the kidney. Methods. CCR6- and CD20-positive B cells were localized in renal biopsies with IgA nephropathy (n = 13), membranous nephropathy (n = 12), crescentic glomerulonephritis (cGN, n = 11) and chronic interstitial nephritis (n = 13), and in pre-implantation biopsies as controls (n = 8). The mRNA expression of CCR6 and the ligand CCL20 was quantified by real-time RT-PCR in 51 renal biopsies of the same disease entities. Results. In the pre-transplant biopsies, CCR6 was expressed by endothelial cells of peritubular and glomerular capillaries. In patients with glomerulonephritis, infiltrating cells were positive particularly in areas of nodular inflammatory cell accumulations. A major part of the CCR6-positive cells were CD20-positive B cells, but a part of the CD3-positive T cells were also found to be positive. The constitutive expression of CCR6 on the endothelium of glomerular capillaries was lost in biopsies with progressive injury. Tubular epithelial cells expressed CCR6 in inflamed kidneys, most commonly on the basolateral side. Conclusions. CCR6 and the corresponding ligand CCL20 might therefore be involved in the recruitment of T and B cells to organized nodular infiltrates in chronic renal inflammation. The functional role of endothelial CCR6 needs to be evaluated in further studie

A complex pattern of chemokine receptor expression is seen in osteosarcoma

<p>Abstract</p> <p>Background</p> <p>Osteosarcoma is the most frequent bone tumor in childhood and adolescence. Patients with primary metastatic disease have a poor prognosis. It is therefore important to better characterize the biology of this tumor to define new prognostic markers or therapeutic targets for tailored therapy. Chemokines and their receptors have been shown to be involved in the development and progression of malignant tumors. They are thought to be active participants in the biology of osteosarcoma. The function of specific chemokines and their receptors is strongly associated with the biological context and microenvironment of their expression. In this report we characterized the expression of a series of chemokine receptors in the complex environment that defines osteosarcoma.</p> <p>Methods</p> <p>The overall level of chemokine receptor mRNA expression was determined using TaqMan RT-PCR of microdissected archival patient biopsy samples. Expression was then verified at the protein level by immunohistochemistry using a series of receptor specific antibody reagents to elucidate the cellular association of expression.</p> <p>Results</p> <p>Expression at the RNA level was found for most of the tested receptors. CCR1 expression was found on infiltrating mononuclear and polynuclear giant cells in the tumor. Cells associated with the lining of intratumoral vessels were shown to express CCR4. Infiltrating mononuclear cells and tumor cells both showed expression of the receptor CCR5, while CCR7 was predominantly expressed by the mononuclear infiltrate. CCR10 was only very rarely detected in few scattered infiltrating cells.</p> <p>Conclusion</p> <p>Our data elucidate for the first time the cellular context of chemokine receptor expression in osteosarcoma. This is an important issue for better understanding potential chemokine/chemokine receptor function in the complex biologic processes that underlie the development and progression of osteosarcoma. Our data support the suggested involvement of chemokines and their receptors in diverse aspects of the biology of osteosarcoma, but also contradict aspects of previous reports describing the expression of these receptors in this tumor.</p

Podoplanin-positive cells are a hallmark of encapsulating peritoneal sclerosis

Background. Encapsulating peritoneal sclerosis (EPS) and simple peritoneal sclerosis are important complications of long-term peritoneal dialysis (PD). Podoplanin is expressed by mesothelial cells and lymphatic vessels, which are involved in inflammatory reactions in the peritoneal cavity. Methods. We studied 69 peritoneal biopsies from patients on PD (n = 16), patients with EPS (n = 18) and control biopsies taken at the time of hernia repair (n = 15) or appendectomy (n = 20). Immunohistochemistry was performed to localize podoplanin. Additionally, markers of endothelial cells, mesothelial cells, myofibroblasts (smooth muscle actin), proliferating cells, and double labelling for smooth muscle actin/podoplanin were used on selected biopsies. Results. Podoplanin was present on the endothelium of lymphatic vessels in the submesothelial fibrous tissue and on mesothelial cells. In patients on PD and in biopsies with appendicitis, the mesothelial cells demonstrated a cuboidal appearance and circumferential podoplanin staining, with gaps between the cells. The number of lymphatic vessels was variable, but prominent at sites of fibrosis. In patients with EPS, a diffuse infiltration of podoplanin-positive cells with a fibroblastic appearance was present in 15 out of 18 biopsies. This pattern was focally present in 3 out of 16 on PD and none in the 35 controls. The podoplanin-positive cells did not express the endothelial marker or the mesothelial marker (calretinin). Conclusions. EPS is characterized by a population of podoplanin and smooth muscle actin double-positive cells. Podoplanin might be a suitable morphological marker supporting the diagnosis and might be involved in the pathogenesis of EP

Differences in the food consumption between kidney stone formers and non-formers in the Swiss Kidney Stone Cohort.

OBJECTIVE Diet has a major influence on the formation and management of kidney stones. However, kidney stone formers' diet is difficult to capture in a large population. Our objective was to describe the dietary intake of kidney stone formers in Switzerland and to compare it to non-stone formers. METHODS We used data from the Swiss Kidney Stone Cohort (n=261), a multicentric cohort of recurrent or incident kidney stone formers with additional risk factors, and a control group of CT-scan proven non-stone formers (n=197). Dieticians conducted two consecutive 24-h dietary recalls, using structured interviews and validated software (GloboDiet). We took the mean consumption per participant of the two 24-h dietary recalls to describe the dietary intake and used two-part models to compare the two groups. RESULTS The dietary intake was overall similar between stone and non-stone formers. However, we identified that kidney stone formers had a higher probability of consuming cakes and biscuits (odds ratio, OR[95% CI] =1.56[1.03; 2.37]) and soft drinks (OR=1.66[1.08; 2.55]). Kidney stone formers had a lower probability of consuming nuts and seeds (OR =0.53[0.35; 0.82]), fresh cheese (OR=0.54[0.30; 0.96]), teas (OR=0.50[0.3; 0.84]), and alcoholic beverages (OR=0.35[0.23; 0.54]), especially wine (OR=0.42[0.27; 0.65]). Furthermore, among consumers, stone formers reported smaller quantities of vegetables (β coeff[95% CI]= - 0.23[- 0.41; - 0.06]), coffee (β coeff= - 0.21[- 0.37; - 0.05]), teas (β coeff= - 0.52[- 0.92; - 0.11]) and alcoholic beverages (β coeff= - 0.34[- 0.63; - 0.06]). CONCLUSION Stone formers reported lower intakes of vegetables, tea, coffee, and alcoholic beverages, more specifically wine, but reported drinking more frequently soft drinks than non-stone formers. For the other food groups, stone formers and non-formers reported similar dietary intakes. Further research is needed to better understand the links between diet and kidney stone formation and develop dietary recommendations adapted to the local settings and cultural habits