Exploring the use of Rasch modelling in "common content" items for multi-site and multi-year assessment.

Rasch modelling is a powerful tool for evaluating item performance, measuring drift in difficulty over time, and comparing students who sat assessments at different times or at different sites. Here, we use data from thirty UK medical schools to describe the benefits of Rasch modelling in quality assurance and the barriers to using it. Sixty "common content" multiple choice items were offered to all UK medical schools in 2016-17, and a further sixty in 2017-18, with five available in both years. Thirty medical schools participated, for sixty total datasets across two sessions, and 14,342 individual sittings. Schools selected items to embed in written assessment near the end of their programmes. We applied Rasch modelling to evaluate unidimensionality, model fit statistics and item quality, horizontal equating to compare performance across schools, and vertical equating to compare item performance across time. Of the sixty sittings, three provided non-unidimensional data, and eight violated goodness of fit measures. Item-level statistics identified potential improvements in item construction and provided quality assurance. Horizontal equating demonstrated large differences in scores across schools, while vertical equating showed item characteristics were stable across sessions. Rasch modelling provides significant advantages in model- and item- level reporting compared to classical approaches. However, the complexity of the analysis and the smaller number of educators familiar with Rasch must be addressed locally for a programme to benefit. Furthermore, due to the comparative novelty of Rasch modelling, there is greater ambiguity on how to proceed when a Rasch model identifies misfitting or problematic data.

Utility of interval kidney biopsy in ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is a rare autoimmune disorder that commonly involves the kidney. Early identification of kidney involvement, assessing treatment-response and predicting outcome are important clinical challenges. Here, we assessed the potential utility of interval kidney biopsy in AAV. METHODS: In a tertiary referral centre with a dedicated vasculitis service, we identified patients with AAV who had undergone interval kidney biopsy, defined as a repeat kidney biopsy (following an initial biopsy showing active AAV) undertaken to determine the histological response in the kidney following induction immunosuppression. We analysed biochemical, histological and outcome data, including times to kidney failure and death for all patients. RESULTS: We identified 57 patients with AAV who underwent at least one interval kidney biopsy (59 interval biopsies in total; median time to interval biopsy ∼130 days). Of the 59 interval biopsies performed, 24 (41%) patients had clinically suspected active disease at time of biopsy which was confirmed histologically in only 42% of cases; 35 (59%) patients were in clinical disease-remission, and this was correct in 97% of cases. The clinician's impression was incorrect in one in four patients. Hematuria at interval biopsy did not correlate with histological activity. Interval biopsy showed fewer acute lesions and more chronic damage compared with initial biopsy and led to immunosuppressive treatment-change in 75% (44/59) of patients. Clinical risk prediction tools tended to operate better using interval biopsy data. CONCLUSION: Interval kidney biopsy is useful for determining treatment-response and subsequent disease management in AAV. It may provide better prognostic information than initial kidney biopsy and should be considered for inclusion into future clinical trials and treatment protocols for patients with AAV.

Effect of remote online exam delivery on student experience and performance in applied knowledge tests.

BACKGROUND: The use of remote online delivery of summative assessments has been underexplored in medical education. Due to the COVID-19 pandemic, all end of year applied knowledge multiple choice question (MCQ) tests at one UK medical school were switched from on campus to remote assessments. METHODS: We conducted an online survey of student experience with remote exam delivery and compared test performance in remote versus invigilated campus-based forms of similar assessments for Year 4 and 5 students across two academic years. RESULTS: Very few students experienced technical or practical problems in completing their exam remotely. Test anxiety was reduced for some students but increased for others. The majority of students preferred the traditional setting of invigilated exams in a computer lab, feeling this ensured an even playing field for all candidates. Mean score was higher for Year 4 students in the remotely-delivered versus campus-based form of the same exam (76.53% [SD 6.57] vs. 72.81% [6.64]; t438.38 = 5.94, p = 0.001; d = 0.56), whereas candidate performance was equivalent across both forms for Year 5 students. CONCLUSIONS: Remote online MCQ exam delivery is an effective and generally acceptable approach to summative assessment, and could be used again in future without detriment to students if onsite delivery is not possible.

Variation in performance on common content items at UK medical schools.

BACKGROUND: Due to differing assessment systems across UK medical schools, making meaningful cross-school comparisons on undergraduate students' performance in knowledge tests is difficult. Ahead of the introduction of a national licensing assessment in the UK, we evaluate schools' performances on a shared pool of "common content" knowledge test items to compare candidates at different schools and evaluate whether they would pass under different standard setting regimes. Such information can then help develop a cross-school consensus on standard setting shared content. METHODS: We undertook a cross-sectional study in the academic sessions 2016-17 and 2017-18. Sixty "best of five" multiple choice 'common content' items were delivered each year, with five used in both years. In 2016-17 30 (of 31 eligible) medical schools undertook a mean of 52.6 items with 7,177 participants. In 2017-18 the same 30 medical schools undertook a mean of 52.8 items with 7,165 participants, creating a full sample of 14,342 medical students sitting common content prior to graduation. Using mean scores, we compared performance across items and carried out a "like-for-like" comparison of schools who used the same set of items then modelled the impact of different passing standards on these schools. RESULTS: Schools varied substantially on candidate total score. Schools differed in their performance with large (Cohen's d around 1) effects. A passing standard that would see 5 % of candidates at high scoring schools fail left low-scoring schools with fail rates of up to 40 %, whereas a passing standard that would see 5 % of candidates at low scoring schools fail would see virtually no candidates from high scoring schools fail. CONCLUSIONS: Candidates at different schools exhibited significant differences in scores in two separate sittings. Performance varied by enough that standards that produce realistic fail rates in one medical school may produce substantially different pass rates in other medical schools - despite identical content and the candidates being governed by the same regulator. Regardless of which hypothetical standards are "correct" as judged by experts, large institutional differences in pass rates must be explored and understood by medical educators before shared standards are applied. The study results can assist cross-school groups in developing a consensus on standard setting future licensing assessment.

Deletion of the myeloid endothelin-B receptor confers long-term protection from angiotensin II-mediated kidney, eye and vessel injury.

The endothelin system may be an important player in hypertensive end-organ injury as endothelin-1 increases blood pressure and is pro-inflammatory. The immune system is emerging as an important regulator of blood pressure and we have shown that the early hypertensive response to angiotensin-II infusion was amplified in mice deficient of myeloid endothelin-B (ETB) receptors (LysM-CreEdnrblox/lox). Hypothesizing that these mice would display enhanced organ injury, we gave angiotensin-II to LysM-CreEdnrblox/lox and littermate controls (Ednrblox/lox) for six weeks. Unexpectedly, LysM-CreEdnrblox/lox mice were significantly protected from organ injury, with less proteinuria, glomerulosclerosis and inflammation of the kidney compared to controls. In the eye, LysM-CreEdnrblox/lox mice had fewer retinal hemorrhages, less microglial activation and less vessel rarefaction. Cardiac remodeling and dysfunction were similar in both groups at week six but LysM-CreEdnrblox/lox mice had better endothelial function. Although blood pressure was initially higher in LysM-CreEdnrblox/lox mice, this was not sustained. A natriuretic switch at about two weeks, due to enhanced ETB signaling in the kidney, induced a hypertensive reversal. By week six, blood pressure was lower in LysM-CreEdnrblox/lox mice than in controls. At six weeks, macrophages from LysM-CreEdnrblox/lox mice were more anti-inflammatory and had greater phagocytic ability compared to the macrophages of Ednrblox/lox mice. Thus, myeloid cell ETB receptor signaling drives this injury both through amplifying hypertension and by inflammatory polarization of macrophages.

Long-term outcomes in elderly patients with ANCA-associated vasculitis.

OBJECTIVE: ANCA-associated vasculitis (AAV) is a small vessel vasculitis that commonly presents in the elderly. However, there are few long-term outcome data for these patients. Here, we assessed long-term outcomes in a single-centre cohort of elderly patients with AAV. Additionally, we tested whether a pre-morbid frailty score could aid prognosis. METHODS: Using a prospectively-compiled dataset, we investigated patients over the age of 65 who presented with AAV between 2005 and 2017 to a regional vasculitis centre. We used a Cox model to determine the factors associated with mortality. We also compared outcomes in pre-specified subgroups stratified by baseline frailty score, ANCA serotype and induction immunosuppression (with cyclophosphamide, rituximab or mycophenolate mofetil used as the main glucocorticoid-sparing agent). RESULTS: 83 patients were included in the study and were followed for a median of 1203 days. Median age was 74 years (range 65-92). Two- and five-year survival in the overall cohort were 83% (95% CI 75, 92%) and 75% (95% CI 65, 86%), respectively. The median cumulative dose of oral prednisolone was 2030 mg during the first three months. Only one patient received intravenous glucocorticoids. Age, frailty score and CRP at presentation were independently associated with mortality; all deaths occurred in patients aged over 75 at presentation. Patients treated with a cyclophosphamide-based induction regimen tended to be younger than those treated with rituximab or mycophenolate mofetil. Survival was better in the cyclophosphamide-treated group. CONCLUSION: In the contemporary era, the overall prognosis of AAV in elderly patients is good. Baseline frailty associates with disease outcomes including mortality. A low-dose glucocorticoid regimen (avoiding intravenous methylprednisolone) can be used to treat AAV effectively in elderly patients.

A novel role for myeloid endothelin-B receptors in hypertension.

AIMS: Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype. METHODS AND RESULTS: In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. CONCLUSION: Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.

Variation in passing standards for graduation-level knowledge items at UK medical schools.

OBJECTIVES: Given the absence of a common passing standard for students at UK medical schools, this paper compares independently set standards for common 'one from five' single-best-answer (multiple-choice) items used in graduation-level applied knowledge examinations and explores potential reasons for any differences. METHODS: A repeated cross-sectional study was conducted. Participating schools were sent a common set of graduation-level items (55 in 2013-2014; 60 in 2014-2015). Items were selected against a blueprint and subjected to a quality review process. Each school employed its own standard-setting process for the common items. The primary outcome was the passing standard for the common items by each medical school set using the Angoff or Ebel methods. RESULTS: Of 31 invited medical schools, 22 participated in 2013-2014 (71%) and 30 (97%) in 2014-2015. Schools used a mean of 49 and 53 common items in 2013-2014 and 2014-2015, respectively, representing around one-third of the items in the examinations in which they were embedded. Data from 19 (61%) and 26 (84%) schools, respectively, met the inclusion criteria for comparison of standards. There were statistically significant differences in the passing standards set by schools in both years (effect sizes (f2 ): 0.041 in 2013-2014 and 0.218 in 2014-2015; both p < 0.001). The interquartile range of standards was 5.7 percentage points in 2013-2014 and 6.5 percentage points in 2014-2015. There was a positive correlation between the relative standards set by schools in the 2 years (Pearson's r = 0.57, n = 18, p = 0.014). Time allowed per item, method of standard setting and timing of examination in the curriculum did not have a statistically significant impact on standards. CONCLUSIONS: Independently set standards for common single-best-answer items used in graduation-level examinations vary across UK medical schools. Further work to examine standard-setting processes in more detail is needed to help explain this variability and develop methods to reduce it.

Benefits of an expanded use of plasma exchange for anti-neutrophil cytoplasmic antibody-associated vasculitis within a dedicated clinical service.

BACKGROUND: Current recommendations for ANCA-associated vasculitis (AAV) support its management within a dedicated clinical service. Therapies for AAV are imperfect with many patients failing to achieve disease control and others experiencing disease relapse. Plasma exchange (PEX) may be beneficial especially when the kidney is involved. METHODS: Within a new, dedicated service we retrospectively assessed, over a 6-year period, the benefits of PEX in two patient cohorts, discriminated by PEX treatment alone. Patients received PEX alongside standard of care if they fulfilled any of the following criteria: 1. serum creatinine >500 µmol/l or dialysis-requiring renal failure, 2. alveolar haemorrhage, 3. renal biopsy showing ≥30 % focal and necrotising lesions ± cellular crescents. Outcome measures included disease remission and relapse, cumulative immunosuppression, and morbidity and mortality. RESULTS: Of 104 new patients, 58 patients received PEX at presentation, 46 did not. Cyclophosphamide and/or rituximab dosing was similar for both groups. Although patients receiving PEX had poorer renal function, a higher C-reactive protein and disease activity score at presentation disease remission rate was similar in both groups (no PEX vs. PEX: 96 % vs. 98 %). The PEX group entered remission quicker (no PEX vs. PEX: 3.9 ± 4.0 vs. 2.8 ± 1.3 months, p < 0.05), with a lower 3-month cumulative glucocorticoid dose (no PEX vs. PEX: 2.5 ± 0.4 vs. 2.3 ± 0.2 g, p < 0.001). Relapse was similar between groups but adverse events lower in the PEX group. CONCLUSIONS: PEX may be of benefit in AAV. Larger, longer randomised controlled trials are now needed.

Utility of renal biopsy in the clinical management of renal disease.

Characterizing chronic kidney disease (CKD) at all stages is an essential part of rational management and the renal biopsy plays a key role in defining the processes involved. There remain no global guidelines available to the renal community on indications for this important diagnostic, prognostic, and relatively safe test. Although most nephrologists recognize several clear indications for a renal biopsy, it is still underutilized. It not only helps the clinician to manage the patient with CKD, but it can also help clarify the epidemiology of CKD, and aid research into the pathobiology of disease with the aim of discovering new therapies. It may be useful for instance in elderly patients with CKD, those with diabetes and presumed 'hypertensive nephropathy', and in some patients with advanced CKD as part of the pretransplant work-up. In some populations (for example, immunoglobulin A nephropathy and ANCA vasculitis), renal biopsy allows disease classification that may predict CKD progression and response to therapy. For the individual, interval renal biopsy may be of use in providing ongoing therapeutic and prognostic information. Molecular advances will change the landscape of renal pathology and add a new dimension to the diagnostic precision of kidney biopsy. Organizing the multiplicity of information available in a renal biopsy to maximize benefits to the patient, as well as to the epidemiologist and researcher, is one of the challenges that face the nephrology community.

Paradoxical effects of heme arginate on survival of myocutaneous flaps.

Ischemia reperfusion injury (IRI) contributes to partial flap and solid organ transplant failure. Heme-oxygenase 1 (HO-1) is an inducible, cytoprotective enzyme which protects against IRI in solid organ transplant models. Heme arginate (HA), a HO-1 inducer, is a promising, translatable, preconditioning agent. This study investigated the effects of preconditioning with HA on the clinical outcome of a myocutaneous IRI model. Forty male Lewis rats were randomized to intravenously receive 1) Control-NaCl, 2) HA, 3) HA and tin mesoporphyrin (SnMP), a HO-1 inhibitor; and 4) SnMP alone. Twenty-four hours later, an in situ transverse rectus abdominis myocutaneous flap was performed under isoflurane anesthesia. Viability of flaps was measured clinically and by laser-Doppler perfusion scanning. In vitro work on human epidermal keratinocytes (HEKa) assessed the effects of HA, SnMP, and the iron chelator desferrioxamine on 1) cytotoxicity, 2) intracellular reactive oxygen species (ROS) concentration, and 3) ROS-mediated DNA damage. In contrast to our hypothesis, HA preconditioning produced over 30% more flap necrosis at 48 h compared with controls (P = 0.02). HA-containing treatments produced significantly worse flap perfusion at all postoperative time points. In vitro work showed that HA is cytotoxic to keratinocytes. This cytotoxicity was independent of HO-1 and was mediated by the generation of ROS by free heme. In contrast to solid organ data, pharmacological preconditioning with HA significantly worsened clinical outcome, thus indicating that this is not a viable approach in free flap research.

The utility of the additive EuroSCORE, RIFLE and AKIN staging scores in the prediction and diagnosis of acute kidney injury after cardiac surgery.

BACKGROUND/AIMS: Acute kidney injury (AKI) following cardiac surgery is a complication associated with high rates of morbidity and mortality. We compared staging systems for the diagnosis of AKI after cardiac surgery, and assessed pre-operative factors predictive of post-operative AKI. METHODS: Clinical data, surgical risk scores, procedure and clinical outcome were obtained on all 4,651 patients undergoing cardiac surgery to the Royal Infirmary of Edinburgh between April 2006 and March 2011, of whom 4,572 had sufficient measurements of creatinine before and after surgery to permit inclusion and analysis. The presence of AKI was assessed using the AKIN and RIFLE criteria. RESULTS: By AKIN criteria, 12.4% of the studied population developed AKI versus 6.5% by RIFLE criteria. Any post-operation AKI was associated with increased mortality from 2.2 to 13.5% (relative risk 7.0, p < 0.001), and increased inpatient stay from a median of 7 (IQR 4) to 9 (IQR 11) days (p < 0.05). Patients identified by AKIN, but not RIFLE, had a mean peak creatinine rise of 34% from baseline and had a significantly lower mortality compared to RIFLE-'Risk' AKI (mortality 6.1 vs. 9.7%; p < 0.05). Pre-operative creatinine, diabetes, NYHA Class IV dyspnoea and EuroSCORE-1 (a surgical risk score) all predicted subsequent AKI on multivariate analysis. EuroSCORE-1 outperformed any single demographic factor in predicting post-operative AKI risk, equating to an 8% increase in relative risk for each additional point. CONCLUSION: AKI after cardiac surgery is associated with delayed discharge and high mortality rates. The AKIN and RIFLE criteria identify patients at a range of AKI severity levels suitable for trial recruitment. The utility of EuroSCORE as a risk stratification tool to identify high AKI-risk subjects for prospective intervention merits further study.

Computed tomography angiography in the diagnosis of ANCA-associated small- and medium-vessel vasculitis.

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically occurs without detectable antineutrophil cytoplasmic antibody. It leads to aneurysm formation by affecting muscular arteries, usually those of medium size but also occasionally those of small size. Kidney involvement is common, leading to reduced glomerular filtration rate, hypertension, rupture of renal arterial aneurysms causing perinephric hematomas, and renal infarctions in those with severe vasculitis. Similar to PAN, microscopic polyangiitis (MPA) leads to aneurysm formation; however, MPA usually is associated with antineutrophil cytoplasmic antibody, and glomerulonephritis is a more common feature of MPA. Although kidney biopsy may show classic vascular changes in both PAN and MPA, this procedure is not without risk of significant bleeding due to aneurysm rupture. We present 2 cases of renal aneurysms that were diagnosed as MPA using computed tomography angiography (CTA), allowing implementation of appropriate immunosuppressive therapy. Follow-up CTA after treatment showed resolution of all previously observed abnormalities. CTA is a useful alternative to kidney biopsy in establishing both the extent of disease in renal aneurysms and allowing for tracking of disease progression and response to therapy.

Endothelin antagonism and its role in the treatment of hypertension.

Hypertension contributes greatly to global disease burden and in many patients current treatments do not adequately control blood pressure (BP). Endothelin-1 (ET-1) is a potent vasoconstrictor that is implicated in the pathogenesis of hypertension, including the hypertension that is often associated with chronic kidney disease (CKD) and the metabolic syndrome. ET receptor antagonists, currently licensed for the treatment of pulmonary arterial hypertension and scleroderma-related digital ulcers, are being investigated for the treatment of hypertension. Clinical trials have addressed the use of ET receptor antagonists as monotherapy in primary hypertension, as an add-on therapy in resistant hypertension and in CKD. This review will evaluate the current evidence regarding the therapeutic potential of ET receptor antagonists in hypertension, as well as highlighting important issues that still need to be addressed.

Infusion of IL-10-expressing cells protects against renal ischemia through induction of lipocalin-2.

Ischemia/reperfusion injury is a leading cause of acute renal failure triggering an inflammatory response associated with infiltrating macrophages, which determine disease outcome. To repair the inflammation we designed a procedure whereby macrophages that overexpress the anti-inflammatory agent interleukin (IL)-10 were adoptively transferred. These bone marrow-derived macrophages were able to increase their intracellular iron pool that, in turn, augmented the expression of lipocalin-2 and its receptors. Infusion of these macrophages into rats after 1 h of reperfusion resulted in localization of the cells to injured kidney tissue, caused increases in regenerative markers, and a notable reduction in both blood urea nitrogen and creatinine. Furthermore, IL-10 therapy decreased the local inflammatory profile and upregulated the expression of pro-regenerative lipocalin-2 and its receptors. IL-10-mediated protection and subsequent renal repair were dependent on the presence of iron and lipocalin-2, since the administration of a neutralizing antibody for lipocalin-2 or administration of IL-10 macrophages pretreated with the iron chelating agent deferoxamine abrogated IL-10-mediated protective effects. Thus, adoptive transfer of IL-10 macrophages to ischemic kidneys blunts acute kidney injury. These effects are mediated through the action of intracellular iron to induce lipocalin-2.

Macrophage/monocyte depletion by clodronate, but not diphtheria toxin, improves renal ischemia/reperfusion injury in mice.

The role of resident renal mononuclear phagocytes in acute kidney injury is controversial with experimental data suggesting both deleterious and protective functions. To help resolve this, we used mice transgenic for the human diphtheria toxin receptor under the control of the CD11b promoter and treated them with diphtheria toxin, or liposomal clodronate, or both to deplete monocyte/mononuclear phagocytes prior to renal ischemia/reperfusion injury. Although either system effectively depleted circulating monocytes and resident mononuclear phagocytes, depletion was most marked in diphtheria toxin-treated mice. Despite this, diphtheria toxin treatment did not protect from renal ischemia. In contrast, mice treated with clodronate exhibited reduced renal failure and acute tubular necrosis, suggesting key differences between these depletion strategies. Clodronate did not deplete CD206-positive renal macrophages and, unlike diphtheria toxin, left resident CD11c-positive cells unscathed while inducing dramatic apoptosis in hepatic and splenic mononuclear phagocyte populations. Abolition of the protected phenotype by administration of diphtheria toxin to clodronate-treated mice suggested that the protective effect of clodronate resulted from the presence of a cytoprotective intrarenal population of mononuclear phagocytes sensitive to diphtheria toxin-mediated ablation.

Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice.

Acute kidney injury (AKI) is common and associated with increased risks of cardiovascular and chronic kidney disease. Causative molecular/physiological pathways are poorly defined. There are no therapies to improve long-term outcomes. An activated endothelin system promotes cardiovascular and kidney disease progression. We hypothesized a causal role for this in the transition of AKI to chronic disease. Plasma endothelin-1 was threefold higher; urine endothelin-1 was twofold higher; and kidney preproendothelin-1, endothelin-A, and endothelin-B receptor message up-regulated in patients with AKI. To show causality, AKI was induced in mice by prolonged ischemia with a 4-week follow-up. Ischemic injury resulted in hypertension, endothelium-dependent and endothelium-independent macrovascular and microvascular dysfunction, and an increase in circulating inflammatory Ly6Chigh monocytes. In the kidney, we observed fibrosis, microvascular rarefaction, and inflammation. Administration of endothelin-A antagonist, but not dual endothelin-A/B antagonist, normalized blood pressure, improved macrovascular and microvascular function, and prevented the transition of AKI to CKD. Endothelin-A blockade reduced circulating and renal proinflammatory Ly6Chigh monocytes and B cells, and promoted recruitment of anti-inflammatory Ly6Clow monocytes to the kidney. Blood pressure reduction alone provided no benefits; blood pressure reduction alongside blockade of the endothelin system was as effective as endothelin-A antagonism in mitigating the long-term sequelae of AKI in mice. Our studies suggest up-regulation of the endothelin system in patients with AKI and show in mice that existing drugs that block the endothelin system, particularly those coupling vascular support and anti-inflammatory action, can prevent the transition of AKI to chronic kidney and cardiovascular disease.

The induction of macrophage hemeoxygenase-1 is protective during acute kidney injury in aging mice.

Aging is thought to be associated with a higher susceptibility to renal ischemia-reperfusion injury (IRI). To study whether defective induction of hemeoxygenase-1 (HO-1, a protective and anti-inflammatory enzyme) might contribute to this, we found that while 12-month-old mice had similar baseline renal function and HO-1 expression, the induction of HO-1 usually seen in ischemia-reperfusion was reduced. This was also associated with worsened renal function and acute tubular necrosis in the aged compared with young mice. In the older mice, heme arginate (HA) induced HO-1 in the cortex and medulla, significantly improved renal function, and reduced tissue injury. Cellular HO-1 induction in the medulla in response to injury or HA treatment was found to be interstitial rather than epithelial, as evidenced by its colocalization with macrophage markers. In vitro, HA treatment of primary macrophages resulted in marked HO-1 induction without impairment of classical activation pathways. Macrophage depletion, caused by diphtheria toxin treatment of 12-month-old CD11b-DTR transgenic animals, resulted in the loss of interstitial HO-1-positive cells and reversal of the protective phenotype of HA treatment. Thus, failure of HO-1 induction following renal IRI worsens structural and functional injury in older mice and represents a therapeutic target in the elderly. Hence, HO-1-positive renal macrophages mediate HA-induced protection in IRI.