Arginase-1 Is Required for Macrophage-Mediated Renal Tubule Regeneration.

BACKGROUND: After kidney injury, macrophages transition from initial proinflammatory activation to a proreparative phenotype characterized by expression of arginase-1 (Arg1), mannose receptor 1 (Mrc1), and macrophage scavenger receptor 1 (Msr1). The mechanism by which these alternatively activated macrophages promote repair is unknown. METHODS: We characterized the macrophage and renal responses after ischemia-reperfusion injury with contralateral nephrectomy in LysM-Cre;Arg1fl/fl mice and littermate controls and used in vitro coculture of macrophages and tubular cells to determine how macrophage-expressed arginase-1 promotes kidney repair. RESULTS: After ischemia-reperfusion injury with contralateral nephrectomy, Arg1-expressing macrophages were almost exclusively located in the outer stripe of the medulla adjacent to injured S3 tubule segments containing luminal debris or casts. Macrophage Arg1 expression was reduced by more than 90% in injured LysM-Cre;Arg1fl/fl mice, resulting in decreased mouse survival, decreased renal tubular cell proliferation and decreased renal repair compared with littermate controls. In vitro studies demonstrate that tubular cells exposed apically to dead cell debris secrete high levels of GM-CSF and induce reparative macrophage activation, with those macrophages in turn secreting Arg1-dependent factor(s) that directly stimulate tubular cell proliferation. CONCLUSIONS: GM-CSF-induced, proreparative macrophages express arginase-1, which is required for the S3 tubular cell proliferative response that promotes renal repair after ischemia-reperfusion injury.

Characterization of temporospatial distribution of renal tubular casts by nephron tracking after ischemia-reperfusion injury.

Renal tubular casts originating from detached epithelial cells after ischemia-reperfusion injury (IRI) can obstruct tubules and negatively impact glomerular filtration rate. Using multiphoton imaging of 400-µm-thick kidney sections, the distribution of casts and morphometric measurement of tubules was performed along the entire nephron for the first time. Tubular nuclei are shed before cell detachment, and visually occlusive casts (grade 3) appeared at 12 h after IRI at the S3/thin descending limb (tDL) junction. Grade 3 casts peaked at 24 h after injury [present in 99% of S3, 78% of tDL, 76% of thin ascending limb (tAL), 60% of medullary thick ascending limb (mTAL), and 10% of connecting tubule segments]. Cast formation in the S3 correlated with selective loss of cell numbers from this tubule segment. By day 3, most mTALs and connecting tubules were cast free, whereas 72% of S3 tubules and 58% of tDLs still contained grade 3 casts. Although bulk phagocytosis of cast material by surviving tubular cells was not observed, mass spectrometry identified large numbers of tryptic peptides in the outer medulla, and trypsin levels were significantly increased in the kidney and urine 24 h after IRI. Administration of either antipain or camostat to inhibit trypsin extended cast burden to the S2, led to sustained accumulation of S3 casts after IRI, but did not affect cast burden in the mTAL or renal function. Our data provide detailed and dynamic mapping of tubular cast formation and resolution after IRI that can inform future interventions to accelerate cast clearance and renal recovery.NEW & NOTEWORTHY This detailed characterization of the dynamic distribution of dead cell debris in ischemically injured kidney tubules reveals which cells in the kidney are most severely injured, when and where tubular casts form, and when (and to a lesser extent, how) they are cleared.

Predictors for moderate to severe acute postoperative pain after total hip and knee replacement.

PURPOSE: The ability to identify and focus care to patients at higher risk of moderate to severe postoperative pain should improve analgesia and patient satisfaction, and may affect reimbursement. We undertook this multi-centre cross-sectional study to identify preoperative risk factors for moderate to severe pain after total hip (THR) and knee (TKR) replacement. METHODS: A total of 897 patients were identified from electronic medical records. Preoperative information and anaesthetic technique was gained by retrospective chart review. The primary outcomes were moderate to severe pain (pain score ≥ 4/10) at rest and with activity on postoperative day one. Logistic regression was performed to identify predictors for moderate to severe pain. RESULTS: Moderate to severe pain was reported by 20 % at rest and 33 % with activity. Predictors for pain at rest were female gender (OR 1.10 with 95 % CI 1.01-1.20), younger age (0.96, 0.94-0.99), increased BMI (1.02, 1.01-1.03), TKR vs. THR (3.21, 2.73-3.78), increased severity of preoperative pain at the surgical site (1.15, 1.03-1.30), preoperative use of opioids (1.63, 1.32-2.01), and general anaesthesia (8.51, 2.13-33.98). Predictors for pain with activity were TKR vs. THR (1.42, 1.28-1.57), increased severity of preoperative pain at the surgical site (1.11, 1.04-1.19), general anaesthesia (9.02, 3.68-22.07), preoperative use of anti-convulsants (1.78, 1.32-2.40) and anti-depressants (1.50, 1.08-2.80), and prior surgery at the surgical site (1.28, 1.05-1.57). CONCLUSIONS: Our findings provide clinical guidance for preoperative stratification of patients for more intensive management potentially including education, nursing staffing, and referral to specialised pain management.

A standardized clinical evaluation of phenotypic diversity in diabetic polyneuropathy.

Diabetic polyneuropathy (DPN) is a major cause of neuropathic pain and a frequent target condition in analgesic treatment trials. Differences in the clinical symptoms and signs associated with DPN suggest distinct pathophysiological mechanisms underlying nerve damage and dysfunction that are likely to have therapeutic relevance. The aim of this study was to develop a tool for the bedside assessment of painful neuropathies such as DPN that captures the diversity of phenotypes. Sixty-one patients with type 2 diabetes and painful neuropathy, 19 patients with painless DPN, 25 patients with type 2 diabetes but no clinical evidence of neuropathy, and 20 healthy control subjects completed a structured interview (47 items) and a standardized physical examination (39 items). After analyzing critical features of pain and painless symptoms and examining the outcome of physical tests of sensory function, we determined principal components of the phenotypic variance among patients. Increased sensitivity to mechanical or thermal stimuli and, to a lesser extent, the sensory quality of pain or paresthesia were the most discriminating elements of DPN phenotypes. Correlation patterns of symptoms and signs indicated the involvement of functionally distinct nerve fiber populations. We combined interview questions and physical tests identifying these differences in a shortened assessment protocol that we named Standardized Evaluation of Pain and Somatosensory Function (StEPS). The protocol StEPS generates a phenotypic profile of patients with neuropathy. Separate intensity ratings for spontaneous painful symptoms and pain evoked by standard stimuli support a detailed documentation of neuropathic pain and its response to analgesic treatment.

Elective change of surgeon during the OR day has an operationally negligible impact on turnover time.

STUDY OBJECTIVE: To compare turnover times for a series of elective cases with surgeons following themselves with turnover times for a series of previously scheduled elective procedures for which the succeeding surgeon differed from the preceding surgeon. DESIGN: Retrospective cohort study. SETTING: University-affiliated teaching hospital. MEASUREMENTS: The operating room (OR) statistical database was accessed to gather 32 months of turnover data from a large academic institution. Turnover time data for the same-surgeon and surgeon-swap groups were batched by month to minimize autocorrelation and achieve data normalization. Two-way analysis of variance (ANOVA) using the monthly batched data was performed with surgeon swapping and changes in procedure category as variables of turnover time. Similar analyses were performed using individual surgical services, hourly time intervals during the surgical day, and turnover frequency per OR as additional covariates to surgeon swapping. MAIN RESULTS: The mean (95% confidence interval [CI]) same-surgeon turnover time was 43.6 (43.2 - 44.0) minutes versus 51.0 (50.5 - 51.6) minutes for a planned surgeon swap (P < 0.0001). This resulted in a difference (95% CI) of 7.4 (6.8 - 8.1) minutes. The exact increase in turnover time was dependent on surgical service, change in subsequent procedure type, time of day when the turnover occurred, and turnover frequency. CONCLUSIONS: The investigated institution averages 2.5 cases per OR per day. The cumulative additional turnover time (far less than one hour per OR per day) for switching surgeons definitely does not allow the addition of another elective procedure if the difference could be eliminated. A flexible scheduling policy allowing surgeon swapping rather than requiring full blocks incurs minimal additional staffed time during the OR day while allowing the schedule to be filled with available elective cases.

A cross-sectional survey on prevalence and risk factors for persistent postsurgical pain 1 year after total hip and knee replacement.

BACKGROUND AND OBJECTIVES: There is a paucity of large multi-institutional surveys to determine the prevalence of and risk factors for persistent pain after total hip (THR) and knee (TKR) replacements. We surveyed a variety of practices and patients and also correlated persistent pain with health-related quality-of-life outcomes. METHODS: From October 10, 2007, to March 15, 2010, patients who had undergone primary THR or TKR with a minimum follow-up of 1 year were identified. A previously published questionnaire to identify persistent postsurgical pain that included a 36-item Short Form Health Survey was mailed to this group. Independent risk factors for persistent pain were identified with logistic regression. RESULTS: Responses from 1030 patients who underwent surgery at some point in time between June 13, 2006, and June 24, 2009, were analyzed (32% response rate). Forty-six percent of patients reported persistent pain (38% after THR and 53% after TKR) with a median average pain score of 3 of 10 and worst pain score of 5. Independent risk factors for persistent pain were female sex (odds ratio [OR], 1.23), younger age (OR, 0.97), prior surgery on hip or knee (OR, 1.39), knee versus hip replacement (OR, 1.65), lower-quality postsurgical pain control (OR, 0.9), and presence of pain in other areas of the body (OR, 2.09). All scores in the 36-item Short Form Health Survey were worse (8%-28% decrease) in patients with persistent postsurgical pain (P < 0.001). CONCLUSIONS: Persistent postsurgical pain is common after THR and TKR and is associated with reduced health-related quality of life, although our survey may be biased by the low response rate and retrospective recall bias. Nonmodifiable risk factors may lead to risk stratification. Severity of acute postoperative pain may be a modifiable risk factor.

Efficacy of opioids for chronic pain: a review of the evidence.

Opioid therapy for chronic pain has been popularized over the past few decades, and a concern has arisen that the analgesic efficacy of opioids is not always maintained over prolonged courses of treatment despite dose escalation and stable pain. Considering the potentially serious adverse effects of opioids, the idea that pain relief could diminish over time may have a significant impact on the decision to embark on this therapy, especially in vulnerable individuals. Possible loss of analgesic efficacy is especially concerning, considering that dependence may make it hard to withdraw opioid therapy even in the face of poor analgesia. This article first reviews the evidence on opioid efficacy when used for the treatment of chronic pain, and concludes that existing evidence suggests that analgesic efficacy, although initially good, is not always sustained during continuous and long-term opioid therapy (months to years). The theoretical basis for loss of analgesic efficacy over time is then examined. Mechanisms for loss of analgesic efficacy proposed are pharmacologic tolerance, opioid-induced hyperalgesia, subtle and intermittent withdrawal, and a number of psychologic factors including loss of the placebo component.