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 inhospital 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. ConclusionPatients 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.

Summary 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.

This study aimed to understand the role of the matrix polysaccharide, hyaluronan (HA), in influencing the scarring process by assessing its impact on regulating fibroblast behavior. Donormatched human oral and dermal fibroblasts were used as models of nonscarring and scarring fibroblast phenotypes, respectively. Phenotypic differences in these two fibroblast populations were assessed and related to differences in HA synthesis and assembly. The two fibroblast populations showed intrinsic differences in their response to the profibrotic cytokine, transforming growth factor-␤ 1 (TGF␤ 1 ), in that oral fibroblasts were resistant to TGF␤ 1 -driven myofibroblastic differentiation. In dermal fibroblasts, differentiation was associated with an induction of HA synthase (HAS1 and HAS2) transcription and assembly of pericellular HA coats. In comparison, resistance to differentiation in oral fibroblasts was associated with failure of induction of HAS1 and HAS2 transcription and failure of pericellular coat assembly. Furthermore, inhibition of HA synthesis in dermal fibroblasts significantly attenuated TGF␤ 1 -mediated differentiation. Interleukin-1␤ stimulation resulted in induction of HAS1 and HAS2 transcription but did not induce phenotypic differentiation or induce HA coat assembly. In addition, neither overexpression nor down-regulation of HAS1 (the isoform uniquely deficient in nonscarring oral fibroblasts) influenced phenotypic differentiation. In conclusion, inhibiting HA synthesis modulates TGF␤ 1 -dependent responses in these cells preventing fibroblast to myofibroblast differentiation. Moreover, HA pericellular coat assembly, rather than HAS isoform expression, appears to be associated with phenotypic differentiation.

This study aims to understand the role of the matrix polysaccharide hyaluronan (HA) in influencing fibroblast proliferation and thereby affecting wound healing outcomes. To determine mechanisms that underlie scarred versus scar-free healing, patient-matched dermal and oral mucosal fibroblasts were used as models of scarring and non-scarring fibroblast phenotypes. Specifically, differences in HA generation between these distinct fibroblast populations have been examined and related to differences in transforming growth factor-␤ 1 (TGF-␤ 1 )-dependent proliferative responses and Smad signaling. There was a differential growth response to TGF-␤ 1 , with it inducing proliferation in dermal fibroblasts but an anti-proliferative response in oral fibroblasts. Both responses were Smad3-dependent. Furthermore, the two fibroblast populations also demonstrated differences in their HA regulation, with dermal fibroblasts generating increased levels of HA, compared with oral fibroblasts. Inhibition of HA synthesis in dermal fibroblasts was shown to abrogate the TGF-␤ 1 -mediated induction of proliferation. Inhibition of HA synthesis also led to an attenuation of Smad3 signaling in dermal fibroblasts. Microarray analysis demonstrated no difference in the genes involved in TGF-␤ 1 signaling between dermal and oral fibroblasts, whereas there was a distinct difference in the pattern of genes involved in HA regulation. In conclusion, these two distinct fibroblast populations demonstrate a differential proliferative response to TGF-␤ 1 , which is associated with differences in HA generation. TGF-␤ 1 regulates proliferation through Smad3 signaling in both fibroblast populations; however, it is the levels of HA generated by the cells that influence the outcome of this response.

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.