Acute kidney injury (AKI) is a complex disorder for which currently there is no accepted definition. Having a uniform standard for diagnosing and classifying AKI would enhance our ability to manage these patients. Future clinical and translational research in AKI will require collaborative networks of investigators drawn from various disciplines, dissemination of information via multidisciplinary joint conferences and publications, and improved translation of knowledge from pre-clinical research. We describe an initiative to develop uniform standards for defining and classifying AKI and to establish a forum for multidisciplinary interaction to improve care for patients with or at risk for AKI. Members representing key societies in critical care and nephrology along with additional experts in adult and pediatric AKI participated in a two day conference in Amsterdam, The Netherlands, in September 2005 and were assigned to one of three workgroups. Each group's discussions formed the basis for draft recommendations that were later refined and improved during discussion with the larger group. Dissenting opinions were also noted. The final draft recommendations were circulated to all participants and subsequently agreed upon as the consensus recommendations for this report. Participating societies endorsed the recommendations and agreed to help disseminate the results. The term AKI is proposed to represent the entire spectrum of acute renal failure. Diagnostic criteria for AKI are proposed based on acute alterations in serum creatinine or urine output. A staging system for AKI which reflects quantitative changes in serum creatinine and urine output has been developed. We describe the formation of a multidisciplinary collaborative network focused on AKI. We have proposed uniform standards for diagnosing and classifying AKI which will need to be validated in future studies. The Acute Kidney Injury Network offers a mechanism for proceeding with efforts to improve patient outcomes.

Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial-mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast-like cells called fibrocytes that are derived from bone-marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen-associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL-13, IL-21, TGF-beta1), chemokines (MCP-1, MIP-1beta), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator-activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis.

/pdf/cellular-and-molecular-mechanisms-of-fibrosis-48v3c6itoz.pdf

Cellular and molecular mechanisms of fibrosis.

https://www.rmaoem.org/Pdf%20docs/Nanotubes-pulm%20toxicity.pdf

Pulmonary Toxicity of Single-Wall Carbon Nanotubes in Mice 7 and 90 Days After Intratracheal Instillation

Nephrogenic fibrosing dermopathy (NFD) is an acquired, idiopathic disorder that is observed in patients with renal disease. Most patients with NFD have undergone dialysis for renal failure [1,2]. It tends to affect mostly the middle-aged. An association of NFD with coagulation abnormalities, recent vascular surgery or intervention (e.g. shunt/fistula and angioplasty), and presence of antiphospholipid antibodies has been discussed by several authors thus far [1,3], but the origin of the disease is still unknown. A more widespread variant of this fibrosing skin disease with involvement of other organs (e.g. lungs, liver, muscles and the heart) is described as nephrogenic systemic fibrosis (NSF) by Leboit [4], Ting et al. [5] and Daram et al. [6]. NFD is characterized clinically by thickening, induration and hardening of the skin. Distinct nodules also can be seen. The (distal) extremities are the most common area of involvement, followed by the trunk, and the face is almost never involved [1]. The diagnosis of NFD is confirmed in a skin biopsy by specific histopathologic features, namely thickened collagen bundles with surrounding clefts, mucin deposition and a proliferation of fibroblasts and elastic fibers. Signs of inflammation are absent, which makes this disorder a distinct entity [1,7]. In this report, nine end stage renal disease patients undergoing magnetic resonance (MR) angiography are presented, in five of whom skin changes of nephrogenic fibrosing dermatopathy became apparent about 2–4 weeks after the administration of gadolinium (Gd)-containing contrast agent for MR. Patients with and without NFD were compared for possible risk factors to develop this skin disease. Gd is thought to be safe as a contrast agent in renal failure. This case series however, demonstrates that Gd–DTPA possibly plays a triggering role in the development of NFD under certain circumstances.

/pdf/gadolinium-a-specific-trigger-for-the-development-of-2ch94tdvpp.pdf

Gadolinium—a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis?

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis in human disease. Since the 2007 JCA Special Issue (Fourth Edition), the Committee has incorporated systematic review and evidence-based approaches in the grading and categorization of apheresis indications. This Seventh Edition of the JCA Special Issue continues to maintain this methodology and rigor to make recommendations on the use of apheresis in a wide variety of diseases/conditions. The JCA Seventh Edition, like its predecessor, has consistently applied the category and grading system definitions in the fact sheets. The general layout and concept of a fact sheet that was used since the fourth edition has largely been maintained in this edition. Each fact sheet succinctly summarizes the evidence for the use of therapeutic apheresis in a specific disease entity. The Seventh Edition discusses 87 fact sheets (14 new fact sheets since the Sixth Edition) for therapeutic apheresis diseases and medical conditions, with 179 indications, which are separately graded and categorized within the listed fact sheets. Several diseases that are Category IV which have been described in detail in previous editions and do not have significant new evidence since the last publication are summarized in a separate table. The Seventh Edition of the JCA Special Issue serves as a key resource that guides the utilization of therapeutic apheresis in the treatment of human disease. J. Clin. Apheresis 31:149-162, 2016. © 2016 Wiley Periodicals, Inc.

Guidelines on the Use of Therapeutic Apheresis in Clinical Practice—Evidence-Based Approach from the Writing Committee of the American Society for Apheresis: The Sixth Special Issue

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(00)02694-5.pdf

Scleromyxoedema-like cutaneous diseases in renal-dialysis patients

Phillip H. Kuo, MD, PhD Emanuel Kanal, MD Ali K. Abu-Alfa, MD Shawn E. Cowper, MD Nephrogenic systemic fibrosis (NSF), described in 2000 (1), is an emerging systemic disorder characterized by widespread tissue fibrosis. Originally known as nephrogenic fibrosing dermopathy because of its dominant cutaneous findings, the nomenclature was revised in recent years to reflect an increased understanding of its systemic effects (1,2). While the precise cause of NSF remains a mystery, it is known to occur only in patients with renal disease– generally in those requiring dialysis. NSF may develop rapidly and can sometimes result in patients becoming confined to a wheelchair within a few weeks. More commonly, the skin thickening is insidious and can be confused clinically with peripheral edema. Pathophysiologically, NSF results in increased tissue deposition of collagen, commonly resulting in thickening and hardening of the skin of the extremities and often culminating in immobility and contractures of the joints. In some patients, there is clinical involvement of other tissues (lung, skeletal muscle, heart, diaphragm, esophagus, etc), although the patient may not be clinically symptomatic (3). While NSF sometimes stabilizes, it rarely spontaneously remits. No consistently effective therapy exists, although rapid correction in renal function (by medical or surgical means) generally results in a cessation of progression and often in a reversal of symptoms (4). With renal dysfunction at the core of this condition, the possibility that renally excreted endogenous or exogenous substances may be triggering NSF has been of great interest. Since NSF appears not to have existed prior to 1997, suspicion that a recently introduced agent might be the culprit has been rampant, but investigation by several authors and by the Centers for Disease Control and Prevention has so far failed to identify a single causative medication (3). Of great interest, the author of a recent article (5) has suggested that administration of intravenous contrast material for magnetic resonance (MR) imaging (ie, gadolinium chelates) has been associated with a small cluster of patients with NSF in Austria (five of nine imaged patients). A Web-based medical advisory originating in Denmark claims that, since January 2002, approximately 400 patients with severely impaired renal function were administered gadolinium-based MR contrast material; 20 patients (5%) subsequently were diagnosed with NSF (6). Other unpublished U.S. experience (S.E.C., October 2006) suggests an approximate incidence of 3% for the development of NSF in the setting of severe renal failure and administration of intravenous contrast material for MR imaging. An international NSF registry at Yale University (New Haven, Conn) maintains records on over 215 patients with NSF worldwide. A survey now underway has revealed that more than 95% of all NSF patients surveyed (currently approximately 100) have been exposed to a gadolinium chelate within 2–3 months prior to disease onset. The majority of the patients were being maintained with dialysis. However, a number of patients with impaired renal function have been reported to the registry, the severity of whose disease has been difficult to determine retrospectively. To the best of our knowledge, the overwhelming majority of known NSF cases at this point ( 90%) represent patients who had previously received gadodiamide (Omniscan; GE Healthcare, Princeton, NJ) (7). Nevertheless, there have been reports of NSF cases associated with other agents. As of October 26, 2006, there have been a total of 57 cases of NSF associated with prior gadolinium-based MR contrast agent administration reported to the U.S. Food and Drug Administration (FDA) Published online before print 10.1148/radiol.2423061640

Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis.

Background Nephrogenic systemic fibrosis (NSF) is a disease of unknown etiology that affects a subset of patients with renal insufficiency. Recent publications suggested an association between exposure to gadolinium-containing contrast agents and subsequent development of NSF. We sought to detect gadolinium within the skin and soft tissue of patients with NSF who were exposed to gadolinium-based contrast. Methods Paraffin-embedded skin and soft tissue from NSF patients exposed to gadolinium, and from negative controls, was provided by the NSF Registry (New Haven, Conn). The tissue was searched for metals using a field emission scanning electron microscope that was equipped with energy dispersive spectroscopy. The presence of gadolinium and other metals was verified through identification of unique and requisite X-ray emission spectra. Results Gadolinium was detected in 4 of 13 tissue specimens from 7 patients with documented NSF who were exposed to gadolinium-based radiographic contrast. No gadolinium was detected in a paraffin-embedded specimen from a negative control. Based upon the known exposure history of patients with detectable gadolinium, a tissue residence time of 4 to 11 months was observed. Limitations As this was a pilot investigation, only a single control specimen and a single histological section from each block of tissue were utilized. Conclusion In this pilot investigation, gadolinium was detected in the tissue of a number of patients with NSF. Although neither dispositive of a pathophysiologic mechanism, nor proof of causation, the detection of gadolinium within tissue of NSF patients is supportive of an epidemiologic association between exposure to gadolinium-containing contrast material and development of disease.

Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.

Circulating fibrocytes: collagen-secreting cells of the peripheral blood.

This report details the histopathologic findings in a unique fibrosing disorder that recently emerged among patients with renal disease. The affected patients were initially identified among recipients of renal transplants at a single institution, but later cases at other centers were identified, and included patients receiving renal dialysis for a variety of different kidney diseases. The cutaneous changes consisted largely of indurated plaques and papules on the extremities and trunk. Systemic findings seen in scleromyxedema, which the condition resembles in some respects, were absent. By routine microscopy, the findings range from a very subtle proliferation of dermal fibroblasts in early lesions, to a florid proliferation of fibroblasts and dendritic cells in fully developed cases. Thick collagen bundles with surrounding clefts are a prominent finding, and a variable increase in dermal mucin and elastic fibers was usually evident with special stains. CD-34 positive dermal dendrocytes were floridly abundant, with dendritic processes aligned with elastic fibers and around collagen bundles in a dense network. Factor XIIIa and CD-68 positive mono-and multinucleated cells are also present in increased numbers. Electron microscopy highlighted increased elastic fibers closely apposed to dendritic cell processes. The entire dermis was commonly involved, with increased spindle cells, collagen, mucin, and elastic fibers extending through the subcutis along the septa of fatty lobules. In some instances, the process resembled a sarcoma on histopathologic examination. The recent emergence of this condition and the apparent clustering of cases in specific dialysis centers initially suggested a possible infectious and/or toxic agent. To date, however, no such agent has been identified. We propose the term "nephrogenic fibrosing dermopathy (NFD)" until a specific cause can be identified.

Shawn E. Cowper

Papers

Scleromyxoedema-like cutaneous diseases in renal-dialysis patients

Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis.

Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis.

Circulating fibrocytes: collagen-secreting cells of the peripheral blood.

Nephrogenic fibrosing dermopathy.