Evening home lighting adversely impacts the circadian system and sleep.

The regular rise and fall of the sun resulted in the development of 24-h rhythms in virtually all organisms. In an evolutionary heartbeat, humans have taken control of their light environment with electric light. Humans are highly sensitive to light, yet most people now use light until bedtime. We evaluated the impact of modern home lighting environments in relation to sleep and individual-level light sensitivity using a new wearable spectrophotometer. We found that nearly half of homes had bright enough light to suppress melatonin by 50%, but with a wide range of individual responses (0-87% suppression for the average home). Greater evening light relative to an individual's average was associated with increased wakefulness after bedtime. Homes with energy-efficient lights had nearly double the melanopic illuminance of homes with incandescent lighting. These findings demonstrate that home lighting significantly affects sleep and the circadian system, but the impact of lighting for a specific individual in their home is highly unpredictable.

A systematic review of the role of C4d in the diagnosis of acute antibody-mediated rejection.

In this study, we conducted a systematic review of the literature to re-evaluate the role of C4d in the diagnosis of acute antibody-mediated rejection of kidney allografts. Electronic databases were searched until September 2013. Eligible studies allowed derivation of diagnostic tables for the performance of C4d by immunofluorescence or immunohistochemistry with comparison to histopathological features of acute antibody-mediated rejection and/or donor-specific antibody (DSA) assays. Of 3492 unique abstracts, 29 studies encompassing 3485 indication and 868 surveillance biopsies were identified. Assessment of C4d by immunofluorescence and immunohistochemistry exhibited slight to moderate agreement with glomerulitis, peritubular capillaritis, solid-phase DSA assays, DSA with glomerulitis, and DSA with peritubular capillaritis. The sensitivity and specificity of C4d varied as a function of C4d and comparator test thresholds. Prognostically, the presence of C4d was associated with inferior allograft survival compared with DSA or histopathology alone. Thus, our findings support the presence of complement-dependent and -independent phenotypes of acute antibody-mediated rejection. Whether the presence of C4d in combination with histopathology or DSA should be considered for the diagnosis of acute antibody-mediated rejection warrants further study.

Gremlin promotes peritoneal membrane injury in an experimental mouse model and is associated with increased solute transport in peritoneal dialysis patients.

The peritoneal membrane becomes damaged in patients on peritoneal dialysis (PD). Gremlin 1 (GREM1) inhibits bone morphogenic proteins (BMPs) and plays a role in kidney development and fibrosis. We evaluated the role of gremlin in peritoneal fibrosis and angiogenesis. In a cohort of 32 stable PD patients, GREM1 concentration in the peritoneal effluent correlated with measures of peritoneal membrane damage. AdGrem1, an adenovirus to overexpress gremlin in the mouse peritoneum, induced submesothelial thickening, fibrosis, and angiogenesis in C57BL/6 mice, which was associated with decreased expression of BMP4 and BMP7. There was evidence of mesothelial cell transition to a mesenchymal phenotype with increased α smooth muscle actin expression and suppression of E-cadherin. Some of the GREM1 effects may be reversed with recombinant BMP7 or a pan-specific transforming growth factor ß (TGF-ß) antibody. Neovascularization was not inhibited with a TGF-ß antibody, suggesting a TGF-ß-independent angiogenic mechanism. Swiss/Jackson Laboratory (SJL) mice, which are resistant to TGF-ß-induced peritoneal fibrosis, responded in a similar fashion to AdGrem1 as did C57BL/6 mice with fibrosis, angiogenesis, and mesothelial-to-mesenchymal transition. GREM1 was associated with up-regulated TGF-ß expression in both SJL and C57BL/6 mice, but SJL mice demonstrated a defective TGF-ß-induced GREM1 expression. In summary, GREM1 induces fibrosis and angiogenesis in mouse peritoneum and is associated with increased solute transport in these PD patients.

Increased recipient body mass index is associated with acute rejection and other adverse outcomes after kidney transplantation.

BACKGROUND: Outcomes of kidney transplant recipients with increased body mass index (BMI) remain controversial. We studied the relationship between BMI and clinically relevant outcomes among kidney transplant recipients at a large center. METHODS: We performed an observational cohort study of all recipients of kidney transplants at our center from January 1, 2000 to December 31, 2010 to determine if increased BMI at transplantation is associated with adverse outcomes, including delayed graft function and biopsy-proven acute rejection (BPAR). Recipient BMI was categorized as <20, 20 to 24.9 (reference), 25 to 29.9, 30 to 34.9, and ≥35 kg/m. Potential confounders were included in logistic and Cox proportional hazards models. RESULTS: A total of 1151 patients were studied. Recipient BMI of 30 to 34.9 and ≥35 kg/m were associated with an increased risk of delayed graft function (odds ratio [95% confidence interval [CI], 1.92 [1.16-3.19] and 4.49 [2.24-9.00], respectively). BMI≥35 kg/m was also associated with an increased risk of BPAR (hazard ratio [HR; 95% CI], 2.43 [1.48-3.99]), all-cause graft failure (HR [95% CI], 1.97 [1.09-3.56]), and death-censored graft failure (HR [95% CI], 2.43 [1.07-5.51]). Adjustment for acute rejection as a time-varying covariate significantly attenuated the association with graft failure endpoints. There was no significant relation between BMI and death with graft function. CONCLUSIONS: Increased BMI at kidney transplantation is a predictor of adverse outcomes, including BPAR. The role of pretransplantation weight reduction in improving graft and patient outcomes requires further study.

Insulin receptor substrate-2 is expressed in kidney epithelium and up-regulated in diabetic nephropathy.

Diabetic nephropathy (DN) is a progressive fibrotic condition that may lead to end-stage renal disease and kidney failure. Transforming growth factor-ß1 and bone morphogenetic protein-7 (BMP7) have been shown to induce DN-like changes in the kidney and protect the kidney from such changes, respectively. Recent data identified insulin action at the level of the nephron as a crucial factor in the development and progression of DN. Insulin requires a family of insulin receptor substrate (IRS) proteins for its physiological effects, and many reports have highlighted the role of insulin and IRS proteins in kidney physiology and disease. Here, we observed IRS2 expression predominantly in the developing and adult kidney epithelium in mouse and human. BMP7 treatment of human kidney proximal tubule epithelial cells (HK-2 cells) increases IRS2 transcription. In addition, BMP7 treatment of HK-2 cells induces an electrophoretic shift in IRS2 migration on SDS/PAGE, and increased association with phosphatidylinositol-3-kinase, probably due to increased tyrosine/serine phosphorylation. In a cohort of DN patients with a range of chronic kidney disease severity, IRS2 mRNA levels were elevated approximately ninefold, with the majority of IRS2 staining evident in the kidney tubules in DN patients. These data show that IRS2 is expressed in the kidney epithelium and may play a role in the downstream protective events triggered by BMP7 in the kidney. The specific up-regulation of IRS2 in the kidney tubules of DN patients also indicates a novel role for IRS2 as a marker and/or mediator of human DN progression.

CCN2/CTGF increases expression of miR-302 microRNAs, which target the TGFß type II receptor with implications for nephropathic cell phenotypes.

Signalling interplay between transforming growth factor-ß (TGFß) and CCN2 [also called connective tissue growth factor (CTGF)] plays a crucial role in the progression of diabetic nephropathy and has been implicated in cellular differentiation. To investigate the potential role of microRNAs (miRNAs) in the mediation of this signalling network, we performed miRNA screening in mesangial cells treated with recombinant human CCN2. Analysis revealed a cohort of 22 miRNAs differentially expressed by twofold or more, including members of the miR-302 family. Target analysis of miRNA to 3'-untranslated regions (3'-UTRs) identified TGFß receptor II (TßRII) as a potential miR-302 target. In mesangial cells, decreased TßRII expression was confirmed in response to CCN2 together with increased expression of miR-302d. TßRII was confirmed as an miR-302 target, and inhibition of miR-302d was sufficient to attenuate the effect of CCN2 on TßRII. Data from the European Renal cDNA Biopsy Bank revealed decreased TßRII in diabetic patients, suggesting pathophysiological significance. In a mouse model of fibrosis (UUO), miR-302d was increased, with decreased TßRII expression and aberrant signalling, suggesting relevance in chronic fibrosis. miR-302d decreased TGFß-induced epithelial mesenchymal transition (EMT) in renal HKC8 epithelial cells and attenuated TGFß-induced mesangial production of fibronectin and thrombospondin. In summary, we demonstrate a new mode of regulation of TGFß by CCN2, and conclude that the miR-302 family has a role in regulating growth factor signalling pathways, with implications for nephropathic cell fate transitions.

Intensive home haemodialysis: benefits and barriers.

Accumulating evidence of the benefits of intensive home haemodialysis has led to increased international interest in this modality as a viable option for renal replacement therapy. Until the late 1970s, haemodialysis was primarily performed at home; however, the development of in-centre and satellite dialysis units and the advent of peritoneal dialysis led to decreased numbers of patients being managed by home haemodialysis. Over the past decade, a move towards once again providing and supporting haemodialysis at home has emerged, due to a desire to offer a more convenient form of dialysis for the patient in a more cost-effective manner. This shift has generated clinical evidence indicating benefits both from receiving haemodialysis at home, and from the option to provide intensive dialysis treatment in this setting. With the development of new home haemodialysis programs, specific patient-related, physician-related and cost-related barriers to their introduction have been encountered, including patient fear of self-cannulation and lack of expert medical knowledge in the area. This Review discusses the benefits and barriers associated with intensive home haemodialysis.

Selenide ions as catalysts for homo- and crossed-Tishchenko reactions of expanded scope.

Selenide ions have been shown to catalyze the Tishchenko reaction for the first time. These catalysts are superior to previously reported thiolate analogues and promote the disproportionation of aldehydes with increased reaction rates and broader scope at lower catalyst loadings and temperatures. Significantly improved catalyst performance was also observed in the aryl selenide mediated crossed intermolecular Tishchenko reaction.

Deletion of Gremlin1 increases cell proliferation and migration responses in mouse embryonic fibroblasts.

Gremlin1 (Grem1) is an antagonist of bone morphogenetic proteins (BMPs) that plays a critical role in embryonic and postnatal development. Grem1 has been implicated as both a promoter and an inhibitor of cell proliferation driven by BMP-4 and other mitogens in a diverse range of cell types. Recent data showed that Grem1 can trigger angiogenesis via vascular endothelial growth factor receptor (VEGFR2) binding, highlighting that the precise modalities of Grem1 signalling require further elucidation. In an attempt to enhance our understanding of the role of Grem1 in cell proliferation, mouse embryonic fibroblasts lacking grem1 (grem1⁻/⁻) were generated. Grem1⁻/⁻ cells showed elevated levels of proliferation in vitro compared to wild-type and grem1⁺/⁻, with accelerated scratch wound repair but no obvious changes in cell cycle profile. Modest increases in BMP-4-stimulated Smad1/5/8 phosphorylation were detected in grem1⁻/⁻ cells, with concomitant modest changes in Smad-dependent gene expression. Surprisingly, levels of ERK phosphorylation were reduced in grem1⁻/⁻ cells compared to wild-type. These data suggest Grem1 is an inhibitor of embryonic fibroblast proliferation in vitro. Furthermore, the signalling pathways causing increased cell proliferation in the absence of Grem1 may involve other pathways distinct from canonical Smad and non-canonical ERK signalling.

Intensive hemodialysis: normalizing the "unphysiology" of conventional hemodialysis?

Interest in intensified hemodialysis (HD) regimens is increasing internationally, as there is growing evidence that they are associated with improved outcomes. Appreciation that conventional hemodialysis (CHD), delivered as 4-hour sessions three times a week, is not providing optimal physiological replacement of renal function has led to the development of intensified dialysis therapies. These include long intermittent hemodialysis typically lasting 6-8 hours and delivered three times a week, short daily hemodialysis, providing more frequent sessions 4-7 days a week lasting 2-3.5 hours, and nocturnal hemodialysis, performed 5-7 days a week for 6-8 hours. Studies evaluating outcomes from these programs have indicated superior results to those achieved with CHD, including favorable modifications of cardiovascular risk factors and improvements in a variety of clinical measures. The objective of this review is to present available evidence supporting the hypothesis that in an attempt to provide a "more normal physiology," intensified HD regimens achieve outcomes superior to those historically achieved with CHD.

CTGF/CCN2 activates canonical Wnt signalling in mesangial cells through LRP6: implications for the pathogenesis of diabetic nephropathy.

We describe the activation of Wnt signalling in mesangial cells by CCN2. CCN2 stimulates phosphorylation of LRP6 and GSK-3ß resulting in accumulation and nuclear localisation of ß-catenin, TCF/LEF activity and expression of Wnt targets. This is coincident with decreased phosphorylation of ß-catenin on Ser 33/37 and increased phosphorylation on Tyr142. DKK-1 and LRP6 siRNA reversed CCN2's effects. Microarray analyses of diabetic patients identified differentially expressed Wnt components. ß-Catenin is increased in type 1 diabetic and UUO mice and in in vitro models of hyperglycaemia and hypertension. These findings suggest that Wnt/CCN2 signalling plays a role in the pathogenesis of diabetic nephropathy.

Allelic depletion of grem1 attenuates diabetic kidney disease.

OBJECTIVE: Gremlin (grem1) is an antagonist of the bone morphogenetic protein family that plays a key role in limb bud development and kidney formation. There is a growing appreciation that altered grem1 expression may regulate the homeostatic constraints on damage responses in diseases such as diabetic nephropathy. RESEARCH DESIGN AND METHODS: Here we explored whether knockout mice heterozygous for grem1 gene deletion (grem1(+/-)) exhibit protection from the progression of diabetic kidney disease in a streptozotocin-induced model of type 1 diabetes. RESULTS: A marked elevation in grem1 expression was detected in the kidneys and particularly in kidney tubules of diabetic wild-type mice compared with those of littermate controls. In contrast, diabetic grem1(+/-) mice displayed a significant attenuation in grem1 expression at 6 months of diabetes compared with that in age- and sex-matched wild-type controls. Whereas the onset and induction of diabetes were similar between grem1(+/-) and wild-type mice, several indicators of diabetes-associated kidney damage such as increased glomerular basement membrane thickening and microalbuminuria were attenuated in grem1(+/-) mice compared with those in wild-type controls. Markers of renal damage such as fibronectin and connective tissue growth factor were elevated in diabetic wild-type but not in grem1(+/-) kidneys. Levels of pSmad1/5/8 decreased in wild-type but not in grem1(+/-) diabetic kidneys, suggesting that bone morphogenetic protein signaling may be maintained in the absence of grem1. CONCLUSIONS: These data identify grem1 as a potential modifier of renal injury in the context of diabetic kidney disease.