237 research outputs found
Dendritic cells in experimental renal inflammation - Part I
No full textDendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. While descriptions of cells with dendritic morphology in rodent kidneys date back to the early 1970s, a network of DCs in the mouse kidney has only recently been described. DCs acquire distinct phenotypic and functional characteristics depending on the microenvironment and the disease stages. Concomitantly, their communication with cells of the adaptive immunity might have tissue-protective or tissue-deleterious consequences. This review summarizes results from recent studies on the role of DCs in experimental renal inflammation.
Copyright © 2011 S. Karger AG, Basel
Dendritic cells in human renal inflammation - Part II
No full textDendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells that act as master regulators of acquired and innate immune responses. Here, we review the available information on their role in human renal inflammation. In the 1980s and early 1990s, major histocompatibility complex class II antigen- (HLA-DR) positive DCs were first described in normal human kidneys and in the interstitium of kidneys from patients with glomerulonephritis. Several DC subtypes were subsequently distinguished based on their expression of CD1c/BDCA-1, CD141/BDCA-3 and CD209/DC-SIGN (in combination with HLA-DR). These cells were almost exclusively found in the tubulointerstitium, with increased numbers seen during glomerulonephritis. It appears that the human renal tubulointerstitium harbors different DC types which allow the collection of both exogenous as well as endogenous antigens. Plasmacytoid DCs have a plasma cell-like morphology and were commonly found within nodular tubulointerstitial infiltrates. Follicular DCs are rarely seen, but show a predominant localization in organized infiltrates. CD207/langerin is a marker for Langerhans cells. Langerin-positive cells have been found in association with the collecting ducts and urothelium. A functional characterization of these subtypes has been hampered by the difficulty of obtaining samples for analysis. However, these studies are clearly required to define the role of DCs and DC subsets in the pathophysiology of renal disease
Nephroprotective effect of the HMG-CoA-reductase inhibitor cerivastatin in a mouse model of progressive renal fibrosis in Alport syndrome
No full textBackground. Alport syndrome is caused by mutations in genes encoding for the alpha 3, alpha 4 or alpha 5 chain of type IV collagen leading to excessive production of fibrotic tissue and end-stage renal failure. HMG-CoA-reductase-inhibitors exhibit pleiotropic effects by which they modulate the production of connective tissue. The aim of this study was to examine the anti-fibrotic effect of the HMG-CoA-reductase-inhibitor, cerivastatin, in COL4A3 knockout mice, an animal model of Alport syndrome with progressive renal fibrosis. Methods. Forty homozygous COL4A3 knockout mice received cerivastatin, starting 28 or 49 days after birth. Mice were sacrificed at day 52 or 66 after birth. Immunohistochemistry against laminin and fibronectin was performed. Inflammatory cell infiltration was determined by F4/80- and CD3-staining. Myofibroblasts were identified by an alpha-smooth muscle actin staining. Expression of the profibrotic cytokines, TGF-beta 1 and CTGF, were determined by immunoblot. Results. The lifespan of treated COL4A3 knockout mice was increased by 28% compared with untreated animals (71 +/- 6 vs 91 +/- 9 days, P < 0.01). Early cerivastatin treatment reduced cholesterol levels (113 +/- 13 vs 141 +/- 19 mmol/l in untreated animals, P < 0.05) and serum urea (164 vs 235 mmol/l, day 66, P < 0.05). Treatment also decreased proteinuria (5.5 vs 12 g/l at day 66, P < 0.05). Deposition of laminin and fibronectin, expression of TGF-beta and CTGF was reduced. Infiltration of T-cells and macrophages as well as myofibroblasts appeared to be reduced in kidneys from cerivastatin-treated mice. Conclusion. Cerivastatin prolongs the lifespan of COL4A3 knockout mice, reduces proteinuria and delays uraemia. These effects are associated with decreased renal fibrosis and a reduction of inflammatory cell infiltration
‐deficient mice with autosomal recessive Alport nephropathy
No full textLack of the alpha 3 or alpha 4 chain of type IV collagen (COL4) causes autosomal recessive Alport nephropathy in humans and mice that is characterized by progressive glomerulosclerosis and tubulointerstitial disease. Renal pathology is associated with chemokine-mediated macrophage infiltrates but their contribution to the progression of Alport nephropathy is unclear. We found Ccl2 to be expressed in increasing amounts during the progression of nephropathy in Col4a3-deficient mice; hence, we blocked Ccl2 with anti-Ccl2 Spiegelmers, biostable L-enantiomeric RNA aptamers suitable for in vivo applications. Ccl2 blockade reduced the recruitment of ex vivo-labelled macrophages into kidneys of Col4a3-deficient mice. We therefore hypothesized that a prolonged course of Ccl2 blockade would reduce renal macrophage counts and prevent renal pathology in Col4a3-deficient mice. Groups of Col4a3-deficient mice received subcutaneous injections of either an anti-mCcl2 Spiegelmer or non-functional control Spiegelmer on alternate days, starting from day 21 or 42 of age. Glomerular and interstitial macrophage counts were found to be reduced with Ccl2 blockade by 50% and 30%, respectively. However, this was not associated with an improvement of glomerular pathology, interstitial pathology, or of overall survival of Col4a3-deficient mice. We conclude that Ccl2 mediates the recruitment of glomerular and interstitial macrophages but this mechanism does not contribute to the progression of Alport nephropathy in Col4a3-deficient mice. Copyright (C) 2008 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd
Chemokines in Renal Diseases
No full textThe chemokines, members of a large family of chemotactic cytokines, act as directional cues for sorting inflammatory cell subsets to sites of inflammation or lymphoid microenvironments. In addition to their effects on migration, chemokines can also activate effector function in leukocytes and are involved in cell proliferation and angiogenesis. Therefore, it is not surprising that chemokines play important roles in a wide range of human diseases, including genetic immunodeficiencies, infections, autoimmune diseases, and malignant tumors. INTRODUCTION Inflammatory cells play pivotal roles in renal injury and renal allograft rejection Chemokines are small, chemotactic cytokines that provide a complex signal system for cell communication between all kinds of cells, including leukocytes The literature on chemokines in kidney diseases currently focuses on (1) chemokines as therapeutic targets, (2) urinary chemokines and chemokine receptors as diagnostic tools, (3) chemokine polymorphisms as predisposing or prognostic factors, and (4) characterization of chemokines and chemokine receptors in human kidney diseases and allograft rejection. In this review, we will start with the basics and follow with these topics primarily focusing on what has been published on the various renal diseases since mid 2003 (for detailed reviews of earlier data see SOME BASIC "CHEMOKINENOLOGY" The human chemokine family consists of over 40 ligands (L) and 19 corresponding receptors (R) Two functionally characterized groups, i.e., inflammatory and homeostatic chemokines, have been described. Inflammatory chemokines like CCL2/MCP-1, CCL5/RANTES, or CXCL10/IP-10 are rapidly upregulated and released by proinflammatory cytokines. Homeostatic chemokines, on the other hand, are involved in tissue homeostasis and cellular recirculation under noninflammatory conditions. The renal literature has focused on inflammatory chemokines, with very little exceptions [24,25,26]. Chemokine receptors are seven, transmembrane-spanning proteins coupled to heterotrimeric G proteins and activate various intracellular pathways like small GTPases and kinases 836 Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 A series of seven, transmembrane, chemokine-binding proteins that do not signal in response to binding and are now referred to as interceptors (chemokine-internalizing receptors) are under study [27]. Two members of this family are DARC (the duffy antigen receptor) and D6. DARC binds both CC as well as CXC chemokines CHEMOKINES AS THERAPEUTIC TARGETS All intrinsic renal cells can express chemokines in response to stress (for details see The MRL(lpr/lpr) mouse is a well-defined model of lupus nephritis [33]. A variety of chemokines are upregulated during the disease course (including CCL2/MCP-1 and CCL5/RANTES), associated with the recruitment of inflammatory cells, both to the glomerular tuft and the tubulointerstitium [34]. CCL2/MCP-1-deficient mice demonstrated a significant improvement of the disease course [35]. Deficiency of the corresponding receptor CCR2 resulted in a reduction in the inflammatory cell recruitment (both T cells and macrophages) and improved renal morphology (Perez de , Unpublished data, J. Am. Soc. Nephrol. 15, 686 A). Gene transfer of an NH2-terminal deletion mutant of the MCP-1 gene (7ND) was used to interfere with CCR2 signaling [36,37]. This approach was shown to reduce renal inflammation and prolonged survival [36]. Treatment with the CCR1 antagonist BX471 was found to reduce blood urea nitrogen levels, interstitial T cell and macrophage accumulation, and decreased interstitial fibrosis in this model [33]. An additional approach designed to interfere with chemokine signaling involved the transfection of an N-terminally truncated CX3CL1/fractalkine gene (Fkn-AT) into a fibroblastoid cell line, which was then injected subcutaneously [38]. MRL/lpr mice treated with Fkn-AT before the onset or during the early stages of lupus nephritis demonstrated a reduction of glomerular hypercellularity, glomerulosclerosis, crescent formation, and vasculitis [38]. While these results demonstrate a beneficial effect of chemokine blockade in the MRL-lpr mouse using various approaches, more needs to be learned about the specific chemokine receptor expression by inflammatory cells infiltrating the glomeruli during human lupus nephritis. The role of macrophage-derived chemokine (CCL22/MDC) and its corresponding receptor (CCR4) has been studied in a nephrotoxic nephritis model in rats [39]. Induction of CCL22/MDC mRNA and protein was detected in nephritic glomeruli. A blockade of CCL22/MDC using specific antibody did not affect the early phase of the disease, but did suppress macrophage recruitment, crescent formation, and deterioration of renal function in the later phase of the disease [39]. Adriamycin nephropathy is a toxic model induced in mice or rats that leads to proteinuria and interstitial fibrosis [40,41]. During the disease course, an increase in expression of chemokines such as CCL5/RANTES and CCL2/MCP-1, and their corresponding receptors, is seen. The induction of autoantibodies directed against CCL5/RANTES and CCL2/MCP-1, achieved through vaccination with naked DNA in rats, resulted in decreased proteinuria, improved creatinine-clearance, conservation of renal morphology, and reduced inflammatory interstitial infiltrates [40]. Accordingly, blocking CCR1 (a receptor for CCL5/RANTES) with a small molecule antagonist decreased interstitial T cell and macrophage accumulation, and reduced interstitial fibroblast accumulation and interstitial fibrosis [41]. To study the role of hepatocyte growth factor (HGF) in renal inflammation, rats with subtotal nephrectomy were treated with recombinant HGF or with a blocking antibody against HGF [42]. HGF treatment reduced tubular CCL2/MCP-1 and CCL5/RANTES expression and decreased inflammatory cell recruitment. Blocking endogenous HGF had the opposite effect [42]. Therefore, the beneficial effects of 837 Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 HGF in progressive renal injury may be mediated, in part, through reduction of selective chemokine expression. Unilateral ureter obstruction is commonly used as a rapid model of interstitial fibrosis in mice Collagen 4A3-deficient mice develop progressive renal failure, mimicking human Alports syndrome Ischemia/reperfusion (I/R) injury promotes delayed graft function and is a major obstacle to longterm renal allograft survival. In a rat I/R model (4-h cold ischemia), the induction of CINC (a rat homolog of CXCL8/IL-8) was associated with granulocyte recruitment As with any effective agent, chemokine antagonists may have adverse effects related to specific function of the chemokine in other systems, to unspecific interactions, or organ toxicity. Met-RANTES and AOP-RANTES, two CCL5/RANTES-based functional antagonists, have been found to aggravate glomerular damage and proteinuria in mice with immune complex glomerulonephritis, despite a reduction of glomerular leukocyte infiltration CHARACTERIZATION OF CHEMOKINES AND CHEMOKINE RECEPTORS IN HUMAN KIDNEY DISEASES AND ALLOGRAFT REJECTION It is now generally accepted that the severity of interstitial injury correlates well with renal function and is of prognostic value for glomerular diseases Panzer et al. demonstrated a significant increase of CXCR3-positive cells during acute allograft rejection and a significant induction of the corresponding ligands URINARY CHEMOKINES AND CHEMOKINE RECEPTORS AS DIAGNOSTIC TOOLS CCL2/MCP-1 mRNA and protein measured in the urine of patients with lupus nephritis correlated with the clinical disease activity and the histological activity score As described earlier, CXCR3 and its corresponding ligands are upregulated in patients with cellular renal allograft rejection. Therefore, measuring the corresponding ligands might represent a potential tool for the surveillance of allograft damage. In a baboon model of renal allograft rejection, the urinary excretion of CXCL9/Mig and CXCL10/IP-10 was significantly increased during acute allograft rejection and was found to rise before an increase in serum creatinine was seen These results build on reports, dating back to the middle of the 90s, that demonstrate that the measurement of chemokines in the urine may represent an important tool in clinical nephrology. The clinical application has not been reached and larger, prospective studies are clearly needed to demonstrate clinical applicability and the impact on disease courses. Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 839 CHEMOKINE POLYMORPHISMS AS PREDISPOSING OR PROGNOSTIC FACTORS Genetic variations including single nucleotide polymorphisms (SNPs) in chemokines or chemokine receptors have been linked to diverse inflammatory diseases. It is thought that these variations may change the tissue response to injury or the release of chemokines by infiltrating cells. Several polymorphisms of chemokine and chemokine receptor genes of the host are linked to the course of allograft dysfunction after renal transplantation The CCR5Delta32 mutation has also been associated with a better renal outcome in patients with IgA nephropathy No association was found with -2518(A/G) MCP-1 or an additional RANTES/CCL5 polymorphism at -403 (G/A) and the course of IgA nephropathy In a prospective study, Böger et al. included 225 Caucasian patients with type 2 diabetes mellitus on dialysis for less than 2 years TOLL-LIKE RECEPTORS, CHEMOKINES, AND RENAL DISEASES Toll-like receptors (TLR) are a family of receptors that bind to pathogen-associated molecular patterns 840 Segerer and Nelson: Chemokines in Renal Diseases TheScientificWorldJOURNAL (2005) 5, 835-844 SUMMARY Promise of chemokine-based therapeutics in renal disease is beginning to show results. Blockades of select receptors appear to reduce the infiltration of specific leukocytes and thereby limit tissue damage. In human glomerular diseases and allograft rejection, both CCR5 and CXCR3 are currently the most promising targets with CCR5 antagonists demonstrating therapeutic activity in patients with HIV infection and other new drugs in the pipeline (e.g., TAC 220) ACKNOWLEDGMENT
The number of patients with severe encapsulating peritoneal sclerosis is decreasing in a large referral center in Germany
No full textDaniel Kitterer,1 Niko Braun,2 M Dominik Alscher,1 Stephan Segerer,3,* Joerg Latus1,* 1Division of General Medicine and Nephrology, Department of Internal Medicine, Robert-Bosch-Hospital, Stuttgart, Germany; 2Nephrology Center Stuttgart, Stuttgart, Germany, 3Division of Nephrology, University Hospital, Zurich, Switzerland *These authors contributed equally to this work Background: Encapsulating peritoneal sclerosis (EPS) is the most severe complication ­associated with long-term peritoneal dialysis (PD). Previous studies noticed a sharp decline in new patients with severe EPS. We investigated the number of severe EPS patients in our large referral center over almost 20 years.Methods: All late-stage EPS patients who underwent major surgery due to extensive symptoms caused by bowel obstruction (vomiting, abdominal pain, and weight loss) between March 1997 and end of December 2015 in our hospital were included in the present study. An index was calculated between the number of patients with severe EPS and the implanted PD catheters in our center.Results: Between 1979 and 2015, a total of 745 PD catheters were implanted in our center, with a steady increase in the numbers between 2003 and 2015. First patient with severe EPS was treated in 1998, then a rise in the number of patients with EPS was present in 2005. The number of patients with EPS peaked in the period of 2010–2012 (15 patients within 3 years). Afterward, both the absolute numbers and the index between the number of patients with severe EPS and the implanted catheters demonstrated a prominent reduction in the next 3-year period from 2013 to 2015.Conclusion: Our data support the hypothesis that there seems to be a decrease of late-stage EPS incidence over the last years, but data about milder or asymptomatic patients are lacking. This should be kept in mind while giving the patients information about different renal replacement therapies at start of dialysis. Keywords: encapsulating peritoneal sclerosis, EPS surgery, decrease of EPS incidenc
Interstitial inflammation in Alport syndrome
No full textThe Alport syndrome is a hereditary glomerular disease linked to structural abnormalities of collagen IV. In a mouse model of Alport syndrome, the interstitial lymphocyte influx was important for disease progression. CXCR3 is a chemokine receptor involved in lymphocyte recruitment to the kidney. We hypothesized that CXCR3-positive T cells might be involved in human Alport syndrome. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded biopsies from 17 patients with Alport syndrome, 10 with immunoglobulin A (IgA) nephropathy, and 11 healthy donor kidneys. We investigated the expression of the alpha5 chain of collagen IV to confirm the morphologic diagnosis, the chemokine receptor CXCR3 and CD3-positive T cells. Alport syndrome biopsies demonstrated a complete loss of the alpha5 chain of collagen IV from the glomerular basement membrane and the morphologic features consistent with Alport syndrome on electron microscopy. A prominent number of CXCR3-positive cells were found in the tubulointerstitium. Most of the CXCR3-positive cells were CD3-positive T cells, demonstrated by double-labeling in selected biopsies. The number of CXCR3-positive cells in kidneys with Alport syndrome correlated with serum creatinine (P < .05) and with morphologic features of a progressive disease (eg, interstitial fibrosis, glomerulosclerosis, and tubular atrophy). The severity of interstitial CXCR3-positive cell influx was similar in Alport syndrome as compared to immunoglobulin A nephropathy. The noninflammatory glomerular lesion of Alport syndrome is associated with prominent interstitial accumulation of CD3- and CXCR3-positive lymphocytes. The degree of infiltration correlated with renal function. We speculate that targeting T lymphocytes, for example, by CXCR3 blocking agents, might be a novel approach to inhibit disease progression in patients with Alport syndrome
Loss of collagen-receptor DDR1 delays renal fibrosis in hereditary type IV collagen disease
No full textAlport syndrome is a hereditary type IV collagen disease leading to progressive renal fibrosis, hearing loss and ocular changes. End stage renal failure usually develops during adolescence. COL4A3-/- mice serve as an animal model for progressive renal scarring in Alport syndrome. The present study evaluates the role of Discoidin Domain Receptor 1 (DDR1) in cell-matrix interaction involved in pathogenesis of Alport syndrome including renal inflammation and fibrosis. DDR1/COL4A3 Double-knockouts were compared to COL4A3-/- mice with 50% or 100% expression of DDR1, wildtype controls and to DDR1-/- COL4A3+/+ controls for over 6years. Double-knockouts lived 47% longer, mice with 50% DDR1 lived 29% longer and showed improved renal function (reduction in proteinuria and blood urea nitrogen) compared to animals with 100% DDR1 expression. Loss of DDR1 reduced proinflammatory, profibrotic cells via signaling of TGFbeta, CTGF, NFkappaB and IL-6 and decreased deposition of extracellular matrix. Immunogold-staining and in-situ hybridisation identified podocytes as major players in DDR1-mediated fibrosis and inflammation within the kidney. In summary, glomerular epithelial cells (podocytes) express DDR1. Loss of DDR1-expression in the kidney delayed renal fibrosis and inflammation in hereditary type IV collagen disease. This supports our hypothesis that podocyte-matrix interaction via collagen receptors plays an important part in progression of renal fibrosis in Alport disease. The blockade of collagen-receptor DDR1 might serve as an important new therapeutic concept in progressive fibrotic and inflammatory diseases in the future
A Simple Method to Remove Timing Bias From the Kidney Disease: Improving Global Outcomes Definition and Classification of Acute Kidney Injury
No full textEpidemiology and chronic kidney disease as a cardiovascular risk factor
No full textChronic kidney disease defined by an estimated glomerular filtration rate of less than 60 mL/min or the presence of albuminuria is present in about 10% of the European populations. The risk increases with age, arterial hypertension, and diabetes. Both aspects—reduced estimated glomerular filtration rate, and albuminuria—are major factors associated with the progression of renal failure, cardiovascular events, and all-cause mortality. Patients on dialysis have a 10- to 20-fold increase in the cardiovascular event rate. Furthermore, heart failure and sudden cardiac death are associated with the severity of renal failure.</p
- …
