Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.

It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-β1 (TGF- β1) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop−/− mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.

Elevated p53 expression is associated with several kidney diseases including diabetic nephropathy (DN). However, the mechanisms are unclear. We report that expression levels of transforming growth factor-β1 (TGF-β), p53, and microRNA-192 (miR-192) are increased in the renal cortex of diabetic mice, and this is associated with enhanced glomerular expansion and fibrosis relative to nondiabetic mice. Targeting miR-192 with locked nucleic acid–modified inhibitors in vivo decreases expression of p53 in the renal cortex of control and streptozotocin-injected diabetic mice. Furthermore, mice with genetic deletion of miR-192 in vivo display attenuated renal cortical TGF-β and p53 expression when made diabetic, and have reduced renal fibrosis, hypertrophy, proteinuria, and albuminuria relative to diabetic wild-type mice. In vitro promoter regulation studies show that TGF-β induces reciprocal activation of miR-192 and p53, via the miR-192 target Zeb2, leading to augmentation of downstream events related to DN. Inverse correlation between miR-192 and Zeb2 was observed in glomeruli of human subjects with early DN, consistent with the mechanism seen in mice. Our results demonstrate for the first time a TGF-β–induced feedback amplification circuit between p53 and miR-192 related to the pathogenesis of DN, and that miR-192–knockout mice are protected from key features of DN.

Studies suggest that estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) may have different associations with colorectal cancer (CRC) risk, but data are conflicting. Prior meta-analyses did not distinguish between ET and EPT. We conducted a meta-analysis to summarize the relative risks (RR) of CRC due to ET versus EPT among peri-or postmenopausal women. From a total of 2,661 articles, four randomized controlled trials, eight cohort and eight case-control studies were included. Variables assessed included study characteristics, duration and recency of menopausal hormone therapy (HT) use, method of assessment of HT use, outcome definition and its ascertainment method. RRs were synthesized by random-effects models. We found that EPT ever use was associated with a decreased risk of CRC (RR 0.74, 95% CI 0.68-0.81), and so was ET ever use (RR 0.79, 95% CI 0.69-0.91). While current use of ET was associated with a significantly reduced risk of CRC (RR 0.70, 95% CI 0.57-0.85), former use was not (RR 0.86, 95%CI 0.67-1.11). Recency did not significantly modify the association between EPT and CRC risk. EPT former use was associated with a lower RR of CRC compared to ET former use (p 5 0.008) but no such difference was observed between EPT and ET current use (p 5 0.12). Overall, we found consistent evidence supporting the association between EPT and CRC risk reduction, regardless of recency. While literature for the association between ET and CRC risk is heterogeneous, our analyses suggest only current use of ET is associated with a decreased CRC risk.Menopausal hormone therapy (HT) is indicated for shortterm control of intolerable menopausal symptoms and it has a limited role in the treatment of osteoporosis for selected woman. While HT was found to increase the risks of venous thromboembolism, breast cancer and stroke, studies have also suggested that it may be associated with a reduced risk of colorectal cancer (CRC).1 Grodstein et al. conducted a meta-analysis of 18 observational studies that summarized the effect of HT on CRC risk, and showed an overall inverse association, with a pooled relative risk (RR) of 0.80 (95% CI 0.74-0.86).2 Another meta-analysis published by Nanda et al. revealed similar results.3 The explanation for the observed association has been controversial, however, because selective prescribing of HT to healthier subjects (i.e., healthy user bias) may have accounted for superior outcomes in the HT group. This concern was partly settled by the Women's Health Initiative (WHI) study, a large-scale randomized controlled trial (RCT), which found that the use of conjugated equine estrogens plus medroxyprogesterone acetate was associated with a reduction in CRC risk. 4 In contrast, one study did not find a significant association between the use of conjugated equine estrogen alone and CRC risk, although the small number of CRC cases may have limited its interpretation and generalizability. 5 In fact, the WHI study results were not directly comparable with previous observational studies an...

TGF-b 1 is a pleotropic growth factor that mediates glomerulosclerosis and podocyte apoptosis, hallmarks of glomerular diseases. The expression of microRNA-21 (miR-21) is regulated by TGF-b 1 , and miR-21 inhibits apoptosis in cancer cells. TGF-b 1 -transgenic mice exhibit accelerated podocyte loss and glomerulosclerosis. We determined that miR-21 expression increases rapidly in cultured murine podocytes after exposure to TGF-b 1 and is higher in kidneys of TGF-b 1 -transgenic mice than wild-type mice. miR-21-deficient TGF-b 1 -transgenic mice showed increased proteinuria and glomerular extracellular matrix deposition and fewer podocytes per glomerular tuft compared with miR-21 wild-type TGF-b 1 -transgenic littermates. Similarly, miR-21 expression was increased in streptozotocin-induced diabetic mice, and loss of miR-21 in these mice was associated with increased albuminuria, podocyte depletion, and mesangial expansion. In cultured podocytes, inhibition of miR-21 was accompanied by increases in the rate of cell death, TGF-b/Smad3-signaling activity, and expression of known proapoptotic miR-21 target genes p53, Pdcd4, Smad7, Tgfbr2, and Timp3. In American-Indian patients with diabetic nephropathy (n=48), albumin-to-creatinine ratio was positively associated with miR-21 expression in glomerular fractions (r=0.6; P,0.001) but not tubulointerstitial fractions (P=0.80). These findings suggest that miR-21 ameliorates TGF-b1 and hyperglycemia-induced glomerular injury through repression of proapoptotic signals, thereby inhibiting podocyte loss. This finding is in contrast to observations in murine models of tubulointerstitial kidney injury but consistent with findings in cancer models. The aggravation of glomerular disease in miR-21-deficient mice and the positive association with albumin-to-creatinine ratio in patients with diabetic nephropathy support miR-21 as a feedback inhibitor of TGF-b signaling and functions.

Low eGFR is associated with reduced performance on executive function. Individuals with poor renal function should be assessed for cognitive impairment. Potential mechanisms are discussed.

The human papillomavirus (HPV) vaccine helps to prevent cervical cancer. However, research indicates that public acceptance of the vaccine is suboptimal. Our aims were to evaluate the willingness of US women to use the HPV vaccine in their daughters, examine their current understanding of HPV, and determine the impact of HPV knowledge and other socio-demographic factors on their willingness to get their daughters vaccinated. Women aged ≥ 18 years were identified from the US Health Information National Trends Survey. We developed a 6-point composite scoring system based on individual responses to HPV-related questions to characterize personal understanding about HPV. Logistic regression models were constructed to explore the influence of the women's HPV knowledge level and additional socio-demographic factors on the willingness to use HPV in their daughters. There were 804 female respondents: mean age was 44.9 (SD = 2.53) years and 73 % were White. In total, 75 % of women indicated they would vaccinate their daughters against HPV. Mean knowledge score was 4.6 (SD = 0.80). While White race was associated with higher willingness to use the vaccine in their daughters (OR = 1.86, p = 0.04), HPV knowledge level was not (OR = 0.47, p = 0.22). Among US women, HPV knowledge level was high, but it was not associated with the willingness to vaccinate their daughters against HPV. Interventions focused on alleviating racial disparities might better modify the use of the HPV vaccine.

Contact with physicians and the quality of this interaction are associated with screening behavior. Interventions to improve these provider-related factors may promote CRC screening.