CD147 mediates the CD44s-dependent differentiation of myofibroblasts driven by transforming growth factor-ß1.

Progressive fibrosis leads to loss of organ function and affects many organs as a result of excessive extracellular matrix production. The ubiquitous matrix polysaccharide hyaluronan (HA) is central to this through association with its primary receptor, CD44, which exists as standard CD44 (CD44s) or multiple splice variants. Mediators such as profibrotic transforming growth factor (TGF)-ß1 and proinflammatory interleukin (IL)-1ß are widely associated with fibrotic progression. TGF-ß1 induces myofibroblast differentiation, while IL-1ß induces a proinflammatory fibroblast phenotype that promotes fibroblast binding to monocyte/macrophages. CD44 expression is essential for both responses. Potential CD44 splice variants involved, however, are unidentified. The TGF-ß1-activated CD44/epidermal growth factor receptor complex induces differentiation of metastatic cells through interactions with the matrix metalloproteinase inducer, CD147. This study aimed to determine the CD44 variants involved in TGF-ß1- and IL-1ß-mediated responses and to investigate the potential profibrotic role of CD147. Using immunocytochemistry and quantitative PCR, standard CD44s were shown to be essential for both TGF-ß1-induced fibroblast/myofibroblast differentiation and IL-1ß-induced monocyte binding. Co-immunoprecipitation identified that CD147 associated with CD44s. Using CD147-siRNA and confocal microscopy, we also determined that incorporation of the myofibroblast marker, αSMA, into F-actin stress fibers was prevented in the absence of CD147 and myofibroblast-dependent collagen gel contraction was inhibited. CD147 did not associate with HA, but removal of HA prevented the association of CD44s with CD147 at points of cell-cell contact. Taken together, our data suggest that CD44s/CD147 colocalization is essential in regulating the mechanical tension required for the αSMA incorporation into F-actin stress fibers that regulates myofibroblast phenotype.

Hyaluronidase-2 Regulates RhoA Signaling, Myofibroblast Contractility, and Other Key Profibrotic Myofibroblast Functions.

Hyaluronidase (HYAL)-2 is a weak, acid-active, hyaluronan-degrading enzyme broadly expressed in somatic tissues. Aberrant HYAL2 expression is implicated in diverse pathology. However, a significant proportion of HYAL2 is enzymatically inactive; thus the mechanisms through which HYAL2 dysregulation influences pathobiology are unclear. Recently, nonenzymatic HYAL2 functions have been described, and nuclear HYAL2 has been shown to influence mRNA splicing to prevent myofibroblast differentiation. Myofibroblasts drive fibrosis, thereby promoting progressive tissue damage and leading to multimorbidity. This study identifies a novel HYAL2 cytoplasmic function in myofibroblasts that is unrelated to its enzymatic activity. In fibroblasts and myofibroblasts, HYAL2 interacts with the GTPase-signaling small molecule ras homolog family member A (RhoA). Transforming growth factor beta 1-driven fibroblast-to-myofibroblast differentiation promotes HYAL2 cytoplasmic relocalization to bind to the actin cytoskeleton. Cytoskeletal-bound HYAL2 functions as a key regulator of downstream RhoA signaling and influences profibrotic myofibroblast functions, including myosin light-chain kinase-mediated myofibroblast contractility, myofibroblast migration, myofibroblast collagen/fibronectin deposition, as well as connective tissue growth factor and matrix metalloproteinase-2 expression. These data demonstrate that, in certain biological contexts, the nonenzymatic effects of HYAL2 are crucial in orchestrating RhoA signaling and downstream pathways that are important for full profibrotic myofibroblast functionality. In conjunction with previous data demonstrating the influence of HYAL2 on RNA splicing, these findings begin to explain the broad biological effects of HYAL2.

Tumor Necrosis Factor-stimulated Gene 6 (TSG-6)-mediated Interactions with the Inter-α-inhibitor Heavy Chain 5 Facilitate Tumor Growth Factor ß1 (TGFß1)-dependent Fibroblast to Myofibroblast Differentiation.

Fibroblasts are central to wound healing and fibrosis through TGFß1-triggered differentiation into contractile, α-smooth muscle actin (α-SMA)-positive myofibroblasts. This is mediated by accumulation of a pericellular matrix of hyaluronan (HA) and the HA-dependent co-localization of CD44 with the epidermal growth factor receptor (EGFR). Interactions of HA with hyaladherins, such as inter-α-inhibitor (IαI) and tumor necrosis factor-stimulated gene-6 (TSG-6), are also essential for differentiation. This study investigated the mechanisms involved. TSG-6 and α-SMA had different kinetics of induction by TGFß1, with TSG-6 peaking before α-SMA Si CD44 or EGFR inhibition prevented differentiation but had no effect on TSG-6 expression. TSG-6 was essential for differentiation, and mAb A38 (preventing IαI heavy chain (HC) transfer), HA-oligosaccharides, cobalt, or Si bikunin prevented TSG-6 activity, preventing differentiation. A38 also prevented the EGFR/CD44 association. This suggested that TSG-6/IαI HC interaction was necessary for the effect of TSG-6 and that HC stabilization of HA initiated the CD44/EGFR association. The newly described HC5 was shown to be the principal HC expressed, and its cell surface expression was prevented by siRNA inhibition of TSG-6 or bikunin. HC5 was released by hyaluronidase treatment, confirming its association with cell surface HA. Finally, HC5 knockdown by siRNA confirmed its role in myofibroblast differentiation. The current study describes a novel mechanism linking the TSG-6 transfer of the newly described HC5 to the HA-dependent control of cell phenotype. The interaction of HC5 with cell surface HA was essential for TGFß1-dependent differentiation of fibroblasts to myofibroblasts, highlighting its importance as a novel potential therapeutic target.

Hyaluronan regulates bone morphogenetic protein-7-dependent prevention and reversal of myofibroblast phenotype.

Hyaluronan (HA) promotes transforming growth factor (TGF)-ß1-driven myofibroblast phenotype. However, HA can also have disease-limiting activity. Bone morphogenetic protein-7 (BMP7) is an antifibrotic cytokine that antagonizes TGF-ß1, and isolated studies have demonstrated that HA can both mediate and modulate BMP7 responses. In this study, we investigated whether BMP7 can modulate HA in a manner that leads to prevention/reversal of TGF-ß1-driven myofibroblast differentiation in human lung fibroblasts. Results demonstrated that BMP7 prevented and reversed TGF-ß1-driven myofibroblast differentiation through a novel mechanism. BMP7 promoted the dissolution and internalization of cell-surface HA into cytoplasmic endosomes. Endosomal HA co-localized with the HA-degrading enzymes, hyaluronidase-1 and hyaluronidase-2 (Hyal2). Moreover, BMP7 showed differential regulation of CD44 standard and variant isoform expression, when compared with TGF-ß1. In particular, BMP7 increased membrane expression of CD44v7/8. Inhibiting CD44v7/8 as well as blocking Hyal2 and the Na(+)/H(+) exchanger-1 at the cell-surface prevented BMP7-driven HA internalization and BMP7-mediated prevention/reversal of myofibroblast phenotype. In summary, a novel mechanism of TGF-ß1 antagonism by BMP7 is shown and identifies alteration in HA as critical in mediating BMP7 responses. In addition, we identify Hyal2 and CD44v7/8 as new potential targets for manipulation in prevention and reversal of fibrotic pathology.

The impact of acute kidney injury in diabetes mellitus.

BACKGROUND: Little data exist on outcome of acute kidney injury (AKI) in diabetes. We describe short-term recovery of renal function, patient mortality and progressive renal dysfunction following AKI in diabetic patients. METHODS: Using the diagnosis of either diabetes or no diabetes as the defining variable, AKI episodes were identified from records of a clinical biochemistry department serving a population of 560 000. Patient co-morbidity and mortality were collated from electronic patient records. Outcomes were compared with a non-diabetic cohort with AKI. RESULTS: Acute kidney injury was identified in 101 diabetic and 392 non-diabetic patients. Patients with diabetes had less severe AKI, compared with the non-diabetic cohort (AKI stage 1 76% vs 55%, P = 0.0006). Overall acute mortality, and mortality adjusted for co-morbidity, was comparable in the diabetic and non-diabetic groups. Recovery to baseline renal function was greater in diabetic patients (87% vs 63% P = 0.001), and the proportion of patients developing progressive chronic kidney disease was lower in the (14%) compared with the non-diabetic cohort (48%, P < 0.00001). CONCLUSIONS: Although acute mortality is comparable following an AKI episode in diabetic patients compared with that associated with AKI in a non-diabetic cohort, for those surviving the acute episode, its impact on renal function is significantly less than in a non-diabetic group.

Interleukin-1ß induces hyaluronan and CD44-dependent cell protrusions that facilitate fibroblast-monocyte binding.

Persistent inflammation is a well-known determinant of progressive tissue fibrosis; however, the mechanisms underlying this process remain unclear. There is growing evidence indicating a role of the cytokine IL-1ß in profibrotic responses. We previously demonstrated that fibroblasts stimulated with IL-1ß increased their generation of the polysaccharide hyaluronan (HA) and increased their expression of the HA synthase enzyme (HAS-2). The aim of this study was to determine the significance of IL-1ß-induced changes in HA and HAS-2 generation. In this study, we found that stimulation of fibroblasts with IL-1ß results in the relocalization of HA associated with the cell to the outer cell membrane, where it forms HAS2- and CD44-dependent cell membrane protrusions. CD44 is concentrated within the membrane protrusions, where it co-localizes with the intracellular adhesion molecule 1. Furthermore, we have identified that these cell protrusions enhance IL-1ß-dependent fibroblast-monocyte binding through MAPK/ERK signaling. Although previous data have indicated the importance of the HA-binding protein TSG-6 in maintaining the transforming growth factor ß1-dependent HA coat, TSG-6 was not essential for the formation of the IL-1ß-dependent HA protrusions, thus identifying it as a key difference between IL-1ß- and transforming growth factor ß1-dependent HA matrices. In summary, these data suggest that IL-1ß-dependent HA generation plays a role in fibroblast immune activation, leading to sequestration of monocytes within inflamed tissue and providing a possible mechanism for perpetual inflammation.

A simple screening test for the detection of erythropoietin antibodies.

Antibody-mediated pure red cell aplasia (PRCA) is a rare complication of erythropoietin (EPO) therapy. Identification and demonstration of functional activity of EPO antibodies required to diagnose this condition is difficult and only performed in selected laboratories worldwide. In this article we report a recent cluster of three cases of antibody-mediated PRCA over a 16-month period in a single center associated with EPREX use. We also describe the use of a simple low-cost inhibitor assay that can be used to screen for PRCA in local laboratories.

Epidemiology and outcome of community-acquired acute kidney injury.

AIMS: Very little data exist regarding community-acquired acute renal injury (CA-AKI). We have identified and characterized a patient cohort with CA-AKI, and documented its impact on renal function and patient mortality. METHODS: Using the database of the Medical Biochemistry Department of the Cardiff and Vale University Health Board we identified all patients with CA-AKI over a 1 month period in 2009. Follow-up biochemical and clinical data were used to determine short-term (3 months) and long-term (3 years) outcomes. Comparisons were made to a random and an age/sex matched group. RESULTS: Patients with CA-AKI were older than a non-AKI cohort (70.3 vs 57.1 years; P < 0.0001), with a 61% male predominance. 38% had pre-existing chronic kidney disease (CKD) compared with 25% in the age- and sex-matched non-CA-AKI cohort (P = 0.007). 54% of CA-AKI were admitted for inpatient care. Admission was associated with a higher incidence of complete recovery of renal function. Mortality at 3 months was 16.5%, and was related to the severity of AKI. Over the 3 years of follow-up 71% of patients with CA-AKI developed progressive CKD which was more likely following incomplete/no recovery of renal function and in the context of pre-existing CKD. Three year mortality was 45%, which was higher than that of the age/sex matched control cohort (15.7%; P < 0.0001), but was not related to the development of progressive CKD. CONCLUSIONS: CA-AKI carries significant implications in terms of both development of progressive renal disease and high long-term patient mortality.

Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

BACKGROUND/AIM: Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). MATERIALS AND METHODS: We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. RESULTS: Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. CONCLUSION: These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.

Protective effect of ischaemic preconditioning on acute and chronic renal damage following ischaemia reperfusion injury: characterisation of fibrosis development after inflammation resolution.

OBJECTIVES: Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD) are increasingly recognised as one disease continuum, rather than distinct entities, and are associated with a huge burden to healthcare services. The leading cause of AKI worldwide is Ischaemia Reperfusion Injury (IRI), most commonly seen in clinical settings of sepsis-driven hypotension. Ischaemic Preconditioning (IPC) is a strategy aimed at reducing the deleterious effects of IRI. The objectives of this study were to demonstrate an efficacious in vivo model of Kidney IRI, and the protective influence of IPC in attenuating AKI and development of renal fibrosis. METHODS: A rat model of bilateral kidney IRI was used: Male Lewis rats (n=84) were assigned to IRI, sham or IPC. In IRI, renal pedicles were clamped for 45 minutes. IPC groups underwent pulsatile IPC prior to IRI. Kidneys were retrieved at 24 hours, 48 hours, 7 days, 14 days and 28 days, and assessed histologically. RESULTS: IRI led to marked AKI (24-48 h) and renal fibrosis development by 28 days. IPC attenuated this damage, with 66% less fibrosis. Interestingly, at 14-days, the histological appearance of both IRI and IPC kidneys was rather similar, potentially representing an important transitional point at which kidneys commit to either fibrosis or recovery. This may provide a suitable inflexion point for introduction of novel anti-fibrotic therapies. CONCLUSIONS: In conclusion, we have characterised a model of kidney injury from acute to chronic phases, allowing detailed mechanistic understanding and which can be manipulated by effective treatment strategies such as IPC.

Calprotectin blockade inhibits long-term vascular pathology following peritoneal dialysis-associated bacterial infection.

Bacterial infections and the concurrent inflammation have been associated with increased long-term cardiovascular (CV) risk. In patients receiving peritoneal dialysis (PD), bacterial peritonitis is a common occurrence, and each episode further increases late CV mortality risk. However, the underlying mechanism(s) remains to be elucidated before safe and efficient anti-inflammatory interventions can be developed. Damage-Associated Molecular Patterns (DAMPs) have been shown to contribute to the acute inflammatory response to infections, but a potential role for DAMPs in mediating long-term vascular inflammation and CV risk following infection resolution in PD, has not been investigated. We found that bacterial peritonitis in mice that resolved within 24h led to CV disease-promoting systemic and vascular immune-mediated inflammatory responses that were maintained up to 28 days. These included higher blood proportions of inflammatory leukocytes displaying increased adhesion molecule expression, higher plasma cytokines levels, and increased aortic inflammatory and atherosclerosis-associated gene expression. These effects were also observed in infected nephropathic mice and amplified in mice routinely exposed to PD fluids. A peritonitis episode resulted in elevated plasma levels of the DAMP Calprotectin, both in PD patients and mice, here the increase was maintained up to 28 days. In vitro, the ability of culture supernatants from infected cells to promote key inflammatory and atherosclerosis-associated cellular responses, such as monocyte chemotaxis, and foam cell formation, was Calprotectin-dependent. In vivo, Calprotectin blockade robustly inhibited the short and long-term peripheral and vascular consequences of peritonitis, thereby demonstrating that targeting of the DAMP Calprotectin is a promising therapeutic strategy to reduce the long-lasting vascular inflammatory aftermath of an infection, notably PD-associated peritonitis, ultimately lowering CV risk.

Hyaluronan facilitates transforming growth factor-ß1-dependent proliferation via CD44 and epidermal growth factor receptor interaction.

Fibroblast proliferation is an early feature of progressive tissue fibrosis and is largely regulated by the cytokine transforming growth factor-ß1 (TGF-ß1). In the oral mucosa, fibroblasts have a unique phenotype and demonstrate healing with no fibrosis/scarring. Our previous studies show that whereas dermal fibroblasts proliferate in response to TGF-ß1, oral fibroblasts have an antiproliferative response to this cytokine. Hyaluronan (HA) was directly linked to this TGF-ß1-dependent response. The aim of this study was to understand the underlying mechanism through which HA regulates TGF-ß-dependent responses. Using patient-matched oral and dermal fibroblasts, we show that TGF-ß1-dependent proliferation is mediated through the HA receptor CD44, whereas the TGF-ß1-mediated antiproliferative response is CD44-independent. Furthermore, overexpression of HAS2 (HA synthase-2) in oral cells modifies their response, and they subsequently demonstrate a proliferative, CD44-dependent response to TGF-ß1. We also show that epidermal growth factor (EGF) and its receptor (EGFR) are essential for TGF-ß1/HA/CD44-dependent proliferation. Increased HA levels promote EGFR and CD44 coupling, potentiating signal transduction through the MAPK/ERK pathway. Thus, in a HA-rich environment, late ERK1/2 activation results from EGFR/CD44 coupling and leads to a proliferative response to TGF-ß1. In comparison, in a non-HA-rich environment, only early ERK1/2 activation occurs, and this is associated with an antiproliferative response to TGF-ß1. In summary, HA facilitates TGF-ß1-dependent fibroblast proliferation through promoting interaction between CD44 and EGFR, which then promotes specific MAPK/ERK activation, inducing cellular proliferation.

Fibroblasts and myofibroblasts in renal fibrosis.

Interstitial fibrosis, associated with extensive accumulation of extracellular matrix constituents in the cortical interstitium, is directly correlated to progression of renal disease. The earliest histological marker of this progression is the accumulation in the interstitium of fibroblasts with the phenotypic appearance of myofibroblasts. These myofibroblasts are contractile cells that express alpha smooth muscle actin and incorporate it into intracellular stress fibres. Although fibroblasts are histologically visible in normal kidneys, there are relatively few of them and proximal tubular epithelial cells predominate. In progressive disease, however, the interstitium becomes filled with myofibroblasts. In this review, we will examine the phenotype and function of fibroblasts and myofibroblasts in the cortical interstitium and the processes that may modulate them.

Modulation of TGFbeta1-dependent myofibroblast differentiation by hyaluronan.

Myofibroblasts are contractile cells that are characterized by the expression of alpha-smooth muscle actin and mediate the closure of wounds and the formation of collagen-rich scars. Their presence in organs such as lungs, liver, and kidney has long been established as a marker of progressive fibrosis. The transforming growth factor beta(1)-driven differentiation of fibroblasts is a major source of myofibroblasts, and recent data have shown that hyaluronan is a major modulator of this process. This study examines this differentiation mechanism in more detail. Transforming growth factor beta(1)-dependent differentiation to the myofibroblastic phenotype was antagonized by the inhibition of hyaluronan synthesis, confirming that hyaluronan was necessary for differentiation. This response, however, was not reproduced by simply adding hyaluronan to fibroblasts, as the results implicated hyaladherins, as well as the macromolecular assembly of de novo hyaluronan, as essential in this process. We previously suggested that there is a relocalization of lipid-raft components during myofibroblastic differentiation. The present study demonstrates that the hyaluronan receptor CD44, the hyaluronidase HYAL 2, and the transforming growth factor beta(1)-receptor ALK5 all relocalized from raft to non-raft locations, which was reversed by the addition of exogenous hyaluronan. These data highlight a role for endogenous hyaluronan in the mediation of myofibroblastic differentiation. While hyaluronan synthesis was both essential and necessary for differentiation, exogenously provided hyaluronan antagonized differentiation, underscoring a pathological role for hyaluronan in such cell fate processes.

Age-related changes in pericellular hyaluronan organization leads to impaired dermal fibroblast to myofibroblast differentiation.

We have previously demonstrated that transforming growth factor-beta1 (TGF-beta1)-mediated fibroblast-myofibroblast differentiation is associated with accumulation of a hyaluronan (HA) pericellular coat. The current study demonstrates failure of fibroblast-myofibroblast differentiation associated with in vitro aging. This is associated with attenuation of numerous TGF-beta1-dependent responses, including HA synthesis and induction of the HA synthase enzyme HAS2 and the hyaladherin tumor necrosis factor-alpha-stimulated gene 6 (TSG-6), which led to an age-related defect in pericellular HA coat assembly. Inhibition of HAS2-dependent HA synthesis by gene silencing, removal of the HA coat by hyaluronidase digestion, or gene silencing of TSG-6 or cell surface receptor CD44 led to abrogation of TGF-beta1-dependent induction of alpha-smooth muscle actin in "young" cells. This result supports the importance of HAS2-dependent HA synthesis and the HA coat during phenotypic activation. Interleukin-1beta stimulation, however, failed to promote phenotypic conversion despite coat formation. A return to basal levels of HA synthesis in aged cells by HAS2 overexpression restored TGF-beta1-dependent induction of TSG-6 and pericellular HA coat assembly. However, this did not lead to the acquisition of a myofibroblast phenotype. Coordinated induction of HAS2 and TSG-6 facilitation of pericellular HA coat assembly is necessary for TGF-beta1-dependent activation of fibroblasts, and both components of this response are impaired with in vitro aging. In conclusion, the HA pericellular coat is integral but not sufficient to correct for the age-dependent defect in phenotypic conversion.

Understanding Electronic AKI Alerts: Characterization by Definitional Rules.

INTRODUCTION: Automated acute kidney injury (AKI) electronic alerts are based on comparing creatinine with historic results. METHODS: We report the significance of AKI defined by 3 "rules" differing in the time period from which the baseline creatinine is obtained, and AKI with creatinine within the normal range. RESULTS: A total of 47,090 incident episodes of AKI occurred between November 2013 and April 2016. Rule 1 (>26 µmol/l increase in creatinine within 48 hours) accounted for 9.6%. Rule 2 (≥50% increase in creatinine within previous 7 days) and rule 3 (≥50% creatinine increase from the median value of results within the last 8-365 days) accounted for 27.3% and 63.1%, respectively. Hospital-acquired AKI was predominantly identified by rules 1 and 2 (71.7%), and community-acquired AKI (86.3%) by rule 3. Stages 2 and 3 were detected by rules 2 and 3. Ninety-day mortality was higher in AKI rule 2 (32.4%) than rule 1 (28.3%, P < 0.001) and rule 3 (26.6%, P < 0.001). Nonrecovery of renal function (90 days) was lower for rule 1 (7.9%) than rule 2 (22.4%, P < 0.001) and rule 3 (16.5%, P < 0.001). We found that 19.2% of AKI occurred with creatinine values within normal range, in which mortality was lower than that in AKI detected by a creatinine value outside the reference range (22.6% vs. 29.6%, P < 0.001). DISCUSSION: Rule 1 could only be invoked for stage 1 alerts and was associated with acute on chronic kidney disease acquired in hospital. Rule 2 was also associated with hospital-acquired AKI and had the highest mortality and nonrecovery. Rule 3 was the commonest cause of an alert and was associated with community-acquired AKI.

Nuclear hyaluronidase 2 drives alternative splicing of CD44 pre-mRNA to determine profibrotic or antifibrotic cell phenotype.

The cell surface protein CD44 is involved in diverse physiological processes, and its aberrant function is linked to various pathologies such as cancer, immune dysregulation, and fibrosis. The diversity of CD44 biological activity is partly conferred by the generation of distinct CD44 isoforms through alternative splicing. We identified an unexpected function for the ubiquitous hyaluronan-degrading enzyme, hyaluronidase 2 (HYAL2), as a regulator of CD44 splicing. Standard CD44 is associated with fibrotic disease, and its production is promoted through serine-arginine-rich (SR) protein-mediated exon exclusion. HYAL2 nuclear translocation was stimulated by bone morphogenetic protein 7, which inhibits the myofibroblast phenotype. Nuclear HYAL2 displaced SR proteins from the spliceosome, thus enabling HYAL2, spliceosome components (U1 and U2 small nuclear ribonucleoproteins), and CD44 pre-mRNA to form a complex. This prevented double-exon splicing and facilitated the inclusion of CD44 exons 11 and 12, which promoted the accumulation of the antifibrotic CD44 isoform CD44v7/8 at the cell surface. These data demonstrate previously undescribed mechanisms regulating CD44 alternative splicing events that are relevant to the regulation of cellular phenotypes in progressive fibrosis.

Regulation of synthesis and roles of hyaluronan in peritoneal dialysis.

Hyaluronan (HA) is a ubiquitous extracellular matrix glycosaminoglycan composed of repeated disaccharide units of alternating D-glucuronic acid and D-N-acetylglucosamine residues linked via alternating ß-1,4 and ß-1,3 glycosidic bonds. HA is synthesized in humans by HA synthase (HAS) enzymes 1, 2, and 3, which are encoded by the corresponding HAS genes. Previous in vitro studies have shown characteristic changes in HAS expression and increased HA synthesis in response to wounding and proinflammatory cytokines in human peritoneal mesothelial cells. In addition, in vivo models and human peritoneal biopsy samples have provided evidence of changes in HA metabolism in the fibrosis that at present accompanies peritoneal dialysis treatment. This review discusses these published observations and how they might contribute to improvement in peritoneal dialysis.

How good are we at managing acute kidney injury in hospital?

INTRODUCTION: Acute kidney injury (AKI) is a common clinical problem associated with adverse outcomes. This study identifies the incidence of AKI in two UK district general hospitals' without on-site renal services and assesses AKI management and level of nephrologist input. METHODS: The AKIN classification was used to identify 1020 AKI patients over 6 months. Data were collated on patient demographics, AKI management and referral to nephrology and intensive care services. Short/long-term renal outcomes were investigated. Patients were followed up for 14 months post-discharge. RESULTS: Incidence of hospital-based AKI was 6.4%. Mean patient age was 73 years. There was 28.1% acute in-hospital mortality with a further 21.6% 14-month mortality. Only 8.3% of patients were referred to nephrology services for in-hospital review, and only 8.1% had outpatient nephrology follow-up. Compliance with the AKI National Confidential Enquiry into Patient Outcomes and Deaths (NCEPOD) recommendations was poor with 32.8% of patients having renal imaging and 15% of patients having acid-base status assessed. NCEPOD compliance improved with nephrology input. Patients referred to nephrology were likely to be younger with pre-existing CKD and severe AKI. 10.5% of AKI episodes were unrecognized. Forty percent of those with unrecognized AKI, (compared with 15% of recognized AKI) developed de novo or progression of pre-existing CKD. CONCLUSION: AKI in DGHs is mostly managed without nephrology input. There are significant shortcomings in AKI recognition and management in this setting. This is associated with poor mortality and long-term CKD. This study supports a need to improve the teaching and training of front-line medical staff in identifying AKI. Additionally, implementation of AKI e-alert systems may encourage early recognition and provide a prompt for renal referral.

Epidemiology and outcomes in community-acquired versus hospital-acquired AKI.

BACKGROUND AND OBJECTIVE: Compared with AKI in hospitalized patients, little is known about patients sustaining AKI in the community and how this differs from AKI in hospital. This study compared epidemiology, risk factors, and short- and long-term outcomes for patients with community-acquired (CA) and hospital-acquired (HA) AKI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 15,976 patients admitted to two district general hospitals between July 11, 2011, and January 15, 2012 were studied. Through use of an electronic database and the AKI Network classification, 686 patients with CA-AKI and 334 patients with HA-AKI were identified. Patients were followed up for 14 months, and data were collated on short-term and long-term renal and patient outcomes. RESULTS: The incidence of CA-AKI among all hospital admissions was 4.3% compared with an incidence of 2.1% of HA-AKI, giving an overall AKI incidence of 6.4%. Patients with CA-AKI were younger than patients with HA-AKI. Risks for developing HA and CA-AKI were similar and included preexisting CKD, cardiac failure, ischemic heart disease, hypertension, diabetes, dementia, and cancer. Patients with CA-AKI were more likely to have stage 3 AKI and had shorter lengths of hospital stay than patients with HA-AKI. Those with CA-AKI had better (multivariate-adjusted) survival than patients with HA-AKI (hazard ratio, 1.8 [95% CI, 1.44-2.13; P<0.001] for HA-AKI group). Mortality for the CA-AKI group was 45%; 43.7% of these deaths were acute in-hospital deaths. Mortality for the HA-AKI group was 62.9%, with 68.1% of these deaths being acute in-hospital deaths. Renal referral rates were low across the cohorts (8.3%). Renal outcomes were similar in both CA-AKI and HA-AKI groups, with 39.4% and 33.6% of patients in both groups developing de novo CKD or progression of preexisting CKD within 14 months, respectively. CONCLUSION: Patients with CA-AKI sustain more severe AKI than patients with HA-AKI. Despite having risk factors similar to those of patients with HA-AKI, patients with CA AKI have better short- and long-term outcomes.