Murine models of renal disease: Possibilities and problems in studies using mutant mice

The elucidation of the pathogenesis of human renal disease at the molecular level has been facilitated by the growing field of gene targeting and the development of mouse strains with single-gene deletions - the `knock-out' mice. Experimental nephrology, therefore, requires well-characterized and reliable models of human renal disease that can be induced reproducibly in mice. Today surgical procedures for the induction of renal ischemia, chronic renal failure, and ureter obstruction are feasible in mice. Models of mesangioproliferative or crescentic glomerulonephritis, glomerulosclerosis, and tubulointerstitial disease are readily available; however, these depend heavily on the mouse genetic background. Attention to the genetic background and appropriate backcrossing are, therefore, of great importance in the design and interpretation of experimental studies, especially in transgenic mice. Simple murine models displaying the clinical features of other human renal diseases such as IgA nephropathy, membranous glomerulonephritis, and renal vasculitis are still lacking. Mouse strains that spontaneously develop distinct renal pathologies similar to lupus nephritis and focal-segmental glomerulosclerosis can be intercrossed with transgenic mice to study the impact of single-gene deletions on the renal phenotype. The present review provides a survey about currently available spontaneous and inducible murine models of renal disease with special attention to problems and future perspectives for their use in transgenic animals. Copyright (C) 2000 S. Karger AG, Basel

Chemokine receptor CCR1: A new target for progressive kidney disease

Infiltrating leukocytes are thought to contribute to the progression of kidney disease. Locally produced chemokines guide circulating leukocytes into the kidney, which renders therapeutic blockade of respective chemokine receptors on the leukocyte surface as potential targets for the inhibition of renal leukocyte recruitment. By using mutant mice and specific antagonists, we found that chemokine receptor CCR1 has non-redundant functions for leukocyte adhesion to activated vascular endothelium and for transendothelial diapedesis. Most importantly, CCR1 blockade with a specific small molecule antagonist can improve injury in several types of progressive kidney disease models, even if treatment is initiated in advanced disease states. Identification of new targets may add to the therapeutic options in chronic kidney disease. Copyright (C) 2005 S. Karger AG, Basel

Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

Innate versus adaptive immunity in kidney immunopathology

Most kidney disorders involve some degree of inflammation, i.e. induction of pro-inflammatory mediators and leukocyte recruitment. But what are the factors that determine inflammation as a trigger or a consequence of kidney injury? Which types of renal inflammation can be targeted by the novel more selective immunosuppressive and anti-inflammatory agents? How to dissect the mechanisms behind innate and adaptive immune responses that are orchestrated inside or outside the kidney but both cause renal immunopathology i.e. renal inflammation? How to dissect leukocytic cell infiltrates into pro-inflammatory leukocytes from anti-inflammatory and pro-regenerative leukocytes? How to dissect leukocytes that support epithelial repair from those that promote renal fibrosis. The term `renal inflammation' has moved far beyond the descriptive category of `mixed leukocytic cell infiltrates' as commonly described in kidney biopsies. It is time to face the complexity of renal inflammation to finally benefit from the new age of novel immunomodulatory medicines

Pigmented villonodular synovitis of the hip in systemic lupus erythematosus: a case report

<p>Abstract</p> <p>Introduction</p> <p>Pigmented villonodular synovitis is a rare disease of unknown etiology mostly affecting the knee and foot. Until now an association with autoimmune diseases has not been reported.</p> <p>Case presentation</p> <p>The diagnosis of systemic lupus erythematosus was made in a 15-year-old Caucasian girl based on otherwise unexplained fatigue, arthralgia, tenosynovitis, leukopenia, low platelets and the presence of antinuclear and deoxyribonucleic antibodies. At the age of 20 a renal biopsy revealed lupus nephritis class IV and she went into complete remission with mycophenolate mofetil and steroids. She was kept on mycophenolate mofetil for maintenance therapy. At the age of 24 she experienced a flare-up of lupus nephritis with nephrotic syndrome and new onset of pain in her right hip. Magnetic resonance imaging, arthroscopy and subtotal synovectomy identified pigmented villonodular synovitis as the underlying diagnosis. Although her systemic lupus erythematosus went into remission with another course of steroids and higher doses of mycophenolate mofetil, the pigmented villonodular synovitis persisted and she had to undergo open synovectomy to control her symptoms.</p> <p>Conclusion</p> <p>Systemic lupus erythematosus is associated with many different musculoskeletal manifestations including synovitis and arthritis. Pigmented villonodular synovitis has not previously been reported in association with systemic lupus erythematosus, but as its etiology is still unknown, the present case raises the question about a causal relationship between systemic lupus erythematosus and pigmented villonodular synovitis.</p

Questions about Chemokine and Chemokine Receptor Antagonism in Renal Inflammation

Chemokines remain attractive therapeutic targets for modulating inflammatory diseases in all areas of medicine including acute and chronic kidney disease. Industry has launched huge programs for the development of chemokine antagonists, and clinical trials with chemokine and chemokine receptor antagonists are ongoing. However, chemokine biology remains an area of unexpected discoveries. Here we discuss a number of questions which need to be addressed to further explore the potential of chemokine antagonism in renal inflammation: Why does renal expression of chemokines and chemokine receptors not always correlate with their functional significance? Why does chemokine antagonism only partially reduce renal leukocyte counts? Will antagonist combinations be more effective in reducing renal inflammation? What are the functional roles of homeostatic chemokines and atypical, nonsignaling chemokine receptors in renal inflammation? And finally, what classes of chemokine antagonists are available to address these questions experimentally? Copyright (C) 2009 S. Karger AG, Base

Lupus nephritis: From pathogenesis to targets for biologic treatment

BACKGROUND/AIMS Lupus nephritis is an organ manifestation of systemic autoimmunity. Current treatment algorithms are still based on unselective immunosuppressive drugs. There is hope that highly selective biological drugs could be as or even more effective but less toxic. A profound understanding of the pathogenesis of lupus nephritis is necessary to identify the optimal molecular targets. METHODS PubMed and www.clincialtrials.gov were searched using 'lupus nephritis' as the key word. RESULTS The pathogenesis of lupus nephritis is based (1) on the mechanisms that lead to loss of tolerance against nuclear autoantigens, i.e. systemic lupus, and then (2) on the mechanisms of immune complex-induced intrarenal inflammation. Systemic lupus develops when genetic variants allow autoimmunization against nuclear autoantigens, e.g. by impairing lymphocyte depletion via apoptosis, opsonization, and rapid phagocytic clearance. This allows endogenous nucleic acids to directly activate Toll-like receptors on dendritic cells or B cells, a process that drives IFN-\textgreeka-driven immunity, antigen presentation, and the activation of autoreactive lymphocyte subsets. Activation of B cells and their maturation to plasma cells promotes autoantibody production and subsequent immune complex glomerulonephritis. Complement and numerous proinflammatory cytokines drive the inflammatory process that can cause kidney injury, scarring, and chronic kidney disease. CONCLUSION Systemic lupus is more a variable syndrome than a single disorder based on heterogeneous genetic variants and complex aberrant immune alterations. This makes it less likely that a single specific biological drug will be as efficient as currently used unselective immunosuppressive drugs. Autoantibody production and intrarenal immune complex formation are the hallmark of lupus nephritis. However, kidney injury and scarring also result from local amplification of tissue inflammation. Therefore, a combination of unselective immunosuppressive and biological drugs that block immune cell recruitment or proinflammatory cytokines may be promising to improve disease outcomes in lupus nephritis

Renal co-morbidity in patients with rheumatic diseases

Renal co-morbidity is common in patients with rheumatic disease based on regular assessment of serum and urine parameters of renal function. When patients present with both arthritis and renal abnormalities the following questions have to be addressed. Is kidney disease a complication of rheumatic disease or its management, or are they both manifestations of a single systemic autoimmune disease? Is rheumatic disease a complication of kidney disease and its management? How do rheumatic disease and kidney disease affect each other even when they are unrelated? The present review provides an overview of how to address these questions in daily practice