Combining an experiential learning model and interprofessional peer-mentoring to improve maternal and neonatal health: Lessons learned from Indonesia.

Background: High maternal-neonatal mortality rate in the East Nusa Tenggara Timur Province, Indonesia, has raised a concern about improving quality health care and prevention. A task force team consisting of the district health office and the corresponding hospital implemented an interprofessional peer mentoring for improving maternal-neonatal health initiative involving various health professionals and community members. This study assesses the effectiveness of the interprofessional peer-mentoring program in improving health-care workers' capacity and community members' awareness of maternal-neonatal health in the primary care setting. Methods: A mixed-methods action research was conducted to measure the effectiveness of the peer-mentoring program. The task force appointed 15 personnel to be trained as peer mentors for 60 mentees from various professions. Peer mentors' perceptions of knowledge and skills improvement were measured before and after the training program. A reflective logbook was then developed to document mentoring activities. Surveys and logbook observations were performed to measure the effectiveness of the 8-month peer-mentoring program. Mentees' capacity and perception were measured before and after the mentoring program. Quantitative data were analyzed using the descriptive statistics and Wilcoxon's paired-rank test, whereas open-ended responses and log-book reflection were analyzed using the content analysis. Results: The peer-mentor training program improved peer mentors' knowledge and readiness from 3.64/5.00 to 4.23/5.00 (P < 0.001). Moreover, mentees viewed the program as effective in improving self-confidence and working capacity in maternal-neonatal health services from 3.47/5.00 to 3.98/5.00 (P < 0.001). Open-ended responses and a reflective logbook revealed that both mentees and peer mentors gained positive learning experiences. Seniority might become an obstacle to the mentoring process since peer mentors reported barriers in engaging elderly mentees due to seniority issues. Discussion: The interprofessional peer-mentoring program was effective in improving both mentors' and mentees' knowledge, self-confidence, and working capacity in maternal-neonatal primary health services and experiential learning. Further observation of the long-term outcomes of the program should be undertaken.

Reactive oxygen species and IRF1 stimulate IFNα production by proximal tubules during ischemic AKI.

We previously reported that expression of the transcription factor interferon regulatory factor 1 (IRF1) is an early, critical maladaptive signal expressed by renal tubules during murine ischemic acute kidney injury (AKI). We now show that IRF1 mediates signals from reactive oxygen species (ROS) generated during ischemic AKI and that these signals ultimately result in production of α-subtypes of type I interferons (IFNαs). We found that genetic knockout of the common type I IFN receptor (IFNARI-/-) improved kidney function and histology during AKI. There are major differences in the spatial-temporal production of the two major IFN subtypes, IFNß and IFNαs: IFNß expression peaks at 4 h, earlier than IFNαs, and continues at the same level at 24 h; expression of IFNαs also increases at 4 h but continues to increase through 24 h. The magnitude of the increase in IFNαs relative to baseline is much greater than that of IFNß. We show by immunohistology and study of isolated cells that IFNß is produced by renal leukocytes and IFNαs are produced by renal tubules. IRF1, IFNαs, and IFNARI were found on the same renal tubules during ischemic AKI. Furthermore, we found that ROS induced IFNα expression by renal tubules in vitro. This expression was inhibited by small interfering RNA knockdown of IRF1. Overexpression of IRF1 resulted in the production of IFNαs. Furthermore, we found that IFNα stimulated production of maladaptive proinflammatory CXCL2 by renal tubular cells. Altogether our data support the following autocrine pathway in renal tubular cells: ROS > IRF1 > IFNα > IFNARI > CXCL2.

Acute kidney injury: a conspiracy of Toll-like receptor 4 on endothelia, leukocytes, and tubules.

Ischemic acute kidney injury (AKI) contributes to considerable morbidity and mortality in hospitalized patients and can contribute to rejection during kidney transplantation. Maladaptive immune responses can exacerbate injury, and targeting these responses holds promise as therapy for AKI. In the last decade, a number of molecules and receptors were identified in the innate immune response to ischemia-reperfusion injury. This review primarily focuses on one pathway that leads to maladaptive inflammation: toll-like receptor 4 (TLR4) and one of its ligands, high mobility group box protein 1 (HMGB1). The temporal-spatial roles and potential therapeutics targeting this particular receptor-ligand interaction are also explored.

Early interleukin 6 production by leukocytes during ischemic acute kidney injury is regulated by TLR4.

Although leukocytes infiltrate the kidney during ischemic acute kidney injury (AKI) and release interleukin 6 (IL6), their mechanism of activation is unknown. Here, we tested whether Toll-like receptor 4 (TLR4) on leukocytes mediated this activation by interacting with high-mobility group protein B1 (HMGB1) released by renal cells as a consequence of ischemic kidney injury. We constructed radiation-induced bone marrow chimeras using C3H/HeJ and C57BL/10ScNJ strains of TLR4 (-/-) mice and their respective TLR4 (+/+) wild-type counterparts and studied them at 4 h after an ischemic insult. Leukocytes adopted from TLR4 (+/+) mice infiltrated the kidneys of TLR4 (-/-) mice, and TLR4 (-/-) leukocytes infiltrated the kidneys of TLR4 (+/+) mice but caused little functional renal impairment in each case. Maximal ischemic AKI required both radiosensitive leukocytes and radioresistant renal parenchymal and endothelial cells from TLR4 (+/+) mice. Only TLR4 (+/+) leukocytes produced IL6 in vivo and in response to HMGB1 in vitro. Thus, following infiltration of the injured kidney, leukocytes produce IL6 when their TLR4 receptors interact with HMGB1 released by injured renal cells. This underscores the importance of TLR4 in the pathogenesis of ischemic AKI.

Bardoxolone methyl (BARD) ameliorates ischemic AKI and increases expression of protective genes Nrf2, PPARγ, and HO-1.

Ischemic acute kidney injury (AKI) triggers expression of adaptive (protective) and maladaptive genes. Agents that increase expression of protective genes should provide a therapeutic benefit. We now report that bardoxolone methyl (BARD) ameliorates ischemic murine AKI as assessed by both renal function and pathology. BARD may exert its beneficial effect by increasing expression of genes previously shown to protect against ischemic AKI, NF-E2-related factor 2 (Nrf2), peroxisome proliferator-activated receptor-γ (PPARγ), and heme oxygenase 1 (HO-1). Although we found that BARD alone or ischemia-reperfusion alone increased expression of these genes, the greatest increase occurred after the combination of both ischemia-reperfusion and BARD. BARD had a different mode of action than other agents that regulate PPARγ and Nrf2. Thus we report that BARD regulates PPARγ, not by acting as a ligand but by increasing the amount of PPARγ mRNA and protein. This should increase ligand-independent effects of PPARγ. Similarly, BARD increased Nrf2 mRNA; this increased Nrf2 protein by mechanisms in addition to the prolongation of Nrf2 protein half-life previously reported. Finally, we localized expression of these protective genes after ischemia and BARD treatment. Using double-immunofluorescence staining for CD31 and Nrf2 or PPARγ, we found increased Nrf2 and PPARγ on glomerular endothelia in the cortex; Nrf2 was also present on cortical peritubular capillaries. In contrast, HO-1 was localized to different cells, i.e., tubules and interstitial leukocytes. Although Nrf2-dependent increases in HO-1 have been described, our data suggest that BARD's effects on tubular and leukocyte HO-1 during ischemic AKI may be Nrf2 independent. We also found that BARD ameliorated cisplatin nephrotoxicity.

Toll-like receptor 4 regulates early endothelial activation during ischemic acute kidney injury.

Ischemic acute kidney injury (AKI) triggers an inflammatory response which exacerbates injury that requires increased expression of endothelial adhesion molecules. To study this further, we used in situ hybridization, immunohistology, and isolated endothelial cells, and found increased Toll-like receptor 4 (TLR4) expression on endothelial cells of the vasa rectae of the inner stripe of the outer medulla of the kidney 4 h after reperfusion. This increase was probably due to reactive oxygen species, known to be generated early during ischemic AKI, because the addition of hydrogen peroxide increased TLR4 expression in MS1 microvascular endothelial cells in vitro. Endothelial TLR4 may regulate adhesion molecule (CD54 and CD62E) expression as they were increased on endothelia of wild-type but not TLR4 knockout mice in vivo. Further, the addition of high-mobility group protein B1, a TLR4 ligand released by injured cells, increased adhesion molecule expression on endothelia isolated from wild-type but not TLR4 knockout mice. TLR4 was localized to proximal tubules in the cortex and outer medulla after 24 h of reperfusion. Thus, at least two different cell types express TLR4, each of which contributes to renal injury by temporally different mechanisms during ischemic AKI.

Successful renal re-transplantation in the presence of pre-existing anti-DQ5 antibodies when there was zero mismatch at class I human leukocyte antigen A, B, & C: a case report.

INTRODUCTION: Hyperacute rejection may be prevented by avoiding the transplantation of kidneys into patients with pre-existing anti-donor Class I human leukocyte antigen antibodies. However, the role of anti-donor-Class II-human leukocyte antigen-DQ antibodies is not established. The question is ever more relevant as more sensitive cross-matching techniques detect many additional antibodies during the final crossmatch. We now report successful renal transplantation of a patient who had pre-existing antibodies against his donor's human leukocyte antigen-DQ5. CASE PRESENTATION: Our patient, a Caucasian man, was 34 years of age when he received his first deceased donor renal transplant. After 8 years, his first transplant failed from chronic allograft dysfunction and an earlier bout of Banff 1A cellular rejection. The second deceased donor kidney transplant was initially allocated to the patient due to a 0 out of 6 mismatch. The B cell crossmatch was mildly positive, while the T Cell crossmatch was negative. Subsequent assays showed that the patient had preformed antibodies for human leukocyte antigen DQ5 against his second donor. Despite having preformed antibodies against the donor, the patient continues to have excellent allograft function two years after his second renal transplant. CONCLUSION: The presence of pre-existing antibodies against human leukocyte antigen DQ5 does not preclude transplantation. The relevance of having other antibodies against class II human leukocyte antigens prior to transplantation remains to be studied.

The inflammatory response to ischemic acute kidney injury: a result of the 'right stuff' in the 'wrong place'?

PURPOSE OF REVIEW: Ischemic acute kidney injury may be exacerbated by an inflammatory response. How injury elicits inflammation remains a major question in understanding acute kidney injury. The present review examines the hypothesis that molecules released by injured cells elicit inflammation. RECENT FINDINGS: After necrotic death, intracellular molecules find their way into the extracellular space. These molecules include heat shock proteins and HMGB1. Receptors for these proteins include TLR4, TLR2, CD91 and RAGE. These proinflammatory mechanisms may be so useful that nature has evolved mechanisms for programming necrotic death via poly(ADP-ribose) polymerase and cyclophilin D. In addition, apoptosis may also elicit inflammation. SUMMARY: The concepts discussed in this review are important for clinical medicine. Drugs and genetic manipulation may ameliorate ischemic kidney injury by regulating the inflammatory response to cell injury.

Bc3h1 myogenic cells produce an infectious ecotropic murine leukemia virus.

cDNAs representing an endogenous C-type ecotropic murine leukemia virus were isolated from a cDNA library constructed to represent mRNAs present in BC3H1 myogenic cells but not in C2C12 myogenic cells. RNA blot hybridization analysis using the cDNA inserts as probes revealed that BC3H1 cells produce MuLV-related transcirpts of at least three different size classes. A polymerase chain reaction enhanced assay for reverse transcriptase activity revealed the presence of reverse transcriptase in a viral pellet from medium conditioned by BC3H1 cells. A fungizone enhanced assay for syncitium formation provided further evidence of ecotropic retroviral particle production. Exposure of 3T3 cells to medium conditioned by BC3H1 cells, using conditions that facilitate infection, resulted in infection of the 3T3 cells, as confirmed by the syncitium formation assay. We conclude that BC3H1 cells produce an infectious ecotropic murine leukemia virus. Whether or not this feature of BC3H1 cells contributes to their inability to express some muscle-specific genes or to carry out myotube formation is unknown. Investigators will want to take into account that BC3H1 cells are virus producers when planning experiments that involve coculture of BC3H1 with other cell types, BC3H1 conditioned medium, retrovirally mediated transfection into BC3H1 cells, or study of the mCAT-1 amino acid transporter (the viral receptor) in BC3H1 cells. BC3H1 cells and the virus they produce may be of interest to those studying retroviral genomes and products and their effects.