The conundrum of contrast-induced acute kidney injury.

More than sixty years have elapsed since contrast induced nephropathy (CIN) was first described in the medical literature. This term has since been extensively explored, with a variety of studies conducted to investigate its incidence and various mechanisms examined to explain its pathophysiology. However, the topic of CIN remains one of controversy with a widely variable and often questionable incidence derived from various studies. The past two decades have seen a surge in reports questioning the existing of CIN altogether and if more harm is actually being caused to patients out of fear of this potential complication. We have attempted to review relevant studies regarding CIN and highlight the key points of its surmised understanding. The review has a higher focus on more recent literature and updates, in order to determine if an accurate estimate can be made on the incidence of CIN. While there was certainly no lack of material available, practically all the studies reviewed were limited by one or more significant drawbacks that limited the reliability of their conclusions regarding CIN. Based on the information reviewed, the strengths and the flaws encountered in other studies can be used to design a randomized control trial that may help in concluding the longstanding debate on this topic. However due to time, financial, and perhaps even ethical constraints such a trial will be difficult to arrange, and so a definitive answer on CI-AKI, and whether it really exist, may continue to elude clinicians.

Utility of Serial Protocol Biopsies Performed After 1 Year in Predicting Long-Term Kidney Allograft Function According to Histologic Phenotype.

OBJECTIVES: Prognostic implications of early protocol biopsies have been studied; however, the value of late protocol biopsy in predicting graft outcome has not been well defined. Here, we compared the effects of early and late protocol biopsy histologic findings in stable kidney allografts and aimed to understand the significance of "borderline" rejection on allograft function. MATERIALS AND METHODS: We studied 261 biopsies from 159 renal transplant recipients who were on a steroid-free, calcineurin inhibitor and mycophenolate mofetil regimen and who received transplants between 2004 and 2012 with mean follow-up of 5 years. Early (between 3 and 9 mo) and subsequent late (between 12 and 24 mo) protocol biopsies were performed. Biopsies were classified as normal, interstitial fibrosis and/or tubular atrophy, subclinical acute rejection with interstitial fibrosis and/or tubular atrophy, and borderline rejection with interstitial fibrosis and/or tubular atrophy. A linear mixed-effects model was used to determine the effects of early and late protocol biopsies on estimated glomerular filtration rate changes, with baseline time for estimated glomerular filtration rate fixed at 12 months. RESULTS: The adjusted model showed that estimated glomerular filtration rate at 3 months, donor age, delayed graft function, and early protocol biopsies were associated with baseline estimated glomerular filtration rate at 12 months. Estimated glomerular filtration rate changes over time were associated with findings of interstitial fibrosis and/or tubular atrophy at early biopsy and subclinical acute rejection and borderline rejection at late biopsy. At last follow-up, final estimated glomerular filtration rate was significantly associated with interstitial fibrosis and/or tubular atrophy at early biopsy and with subclinical acute rejection at late biopsy. CONCLUSIONS: Although early protocol biopsy predicted baseline estimated glomerular filtration rate, late biopsy was important for predicting changes in function over time. In addition, a diagnosis of "borderline" rejection on protocol biopsies predicted long-term graft function.

Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer.

The ligand-activated nuclear receptor pregnane X receptor (PXR) is known to play a role in the regulated expression of drug metabolizing enzymes and transporters. Recent studies suggest a potential clinically relevant role of PXR in breast cancer. However, the relevant pathway or target genes of PXR in breast cancer biology and progression have not yet been fully clarified. In this study, we show that mRNA expression of organic anion transporter polypeptide 1A2 (OATP1A2), a transporter capable of mediating the cellular uptake of estrogen metabolites, is nearly 10-fold greater in breast cancer compared with adjacent healthy breast tissues. Immunohistochemistry revealed exclusive expression of OATP1A2 in breast cancer tissue. Interestingly, treatment of breast cancer cells in vitro with the PXR agonist rifampin induced OATP1A2 expression in a time-dependent and concentration-dependent manner. Consistent with its role as a hormone uptake transporter, induction of OATP1A2 was associated with increased uptake of estrone 3-sulfate. The rifampin response was abrogated after small interfering RNA targeting of PXR. We then identified a PXR response element in the human OATP1A2 promoter, located approximately 5.7 kb upstream of the transcription initiation site. The specificity of PXR-OATP1A2 promoter interaction was confirmed using chromatin immunoprecipitation. Importantly, we used a novel potent and specific antagonist of PXR (A-792611) to show the reversal of the rifampin effect on the cellular uptake of E(1)S. These data provide important new insights into the interplay between a xenobiotic nuclear receptor PXR and OATP1A2 that could contribute to the pathogenesis of breast cancer and may also prove to be heretofore unrecognized targets for breast cancer treatment.