Background: Myocardial injury after noncardiac surgery (MINS) was defined as prognostically relevant myocardial injury due to ischemia that occurs during or within 30 days after noncardiac surgery. The study’s four objectives were to determine the diagnostic criteria, characteristics, predictors, and 30-day outcomes of MINS. Methods: In this international, prospective cohort study of 15,065 patients aged 45 yr or older who underwent in-patient noncardiac surgery, troponin T was measured during the first 3 postoperative days. Patients with a troponin T level of 0.04 ng/ml or greater (elevated “abnormal” laboratory threshold) were assessed for ischemic features (i.e., ischemic symptoms and electrocardiography findings). Patients adjudicated as having a nonischemic troponin elevation (e.g., sepsis) were excluded. To establish diagnostic criteria for MINS, the authors used Cox regression analyses in which the dependent variable was 30-day mortality (260 deaths) and independent variables included preoperative variables, perioperative complications, and potential MINS diagnostic criteria. Results: An elevated troponin after noncardiac surgery, irrespective of the presence of an ischemic feature, independently predicted 30-day mortality. Therefore, the authors’ diagnostic criterion for MINS was a peak troponin T level of 0.03 ng/ml or greater judged due to myocardial ischemia. MINS was an independent predictor of 30-day mortality (adjusted hazard ratio, 3.87; 95% CI, 2.96–5.08) and had the highest population-attributable risk (34.0%, 95% CI, 26.6–41.5) of the perioperative complications. Twelve hundred patients (8.0%) suffered MINS, and 58.2% of these patients would not have fulfilled the universal definition of myocardial infarction. Only 15.8% of patients with MINS experienced an ischemic symptom. Conclusion: Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

Macrophage infiltration of the kidney is a prominent feature associated with the severity of renal injury and progressive renal failure. To determine the influence of macrophages in renal disease models in the absence of endogenous T and B cells, we performed adoptive transfer of macrophages into severe combined immunodeficient (SCID) mice. In this study, macrophages were isolated from the spleens of BALB/c mice and stimulated with lipopolysaccharide to induce classically activated M1 macrophages or with interleukin-4 (IL-4) and IL-13 to induce alternatively activated M2 macrophages. These macrophages were then infused into SCID mice with adriamycin nephropathy; an in vivo model of chronic inflammatory renal disease analogous to human focal segmental glomerulosclerosis. Mice infused with M1 macrophages had a more severe histological and functional injury, whereas M2 macrophage-induced transfused mice had reduced histological and functional injury. Both M1 and M2 macrophages localized preferentially to the area of injury and maintained their phenotypes even after 4 weeks. The protective effect of M2 macrophages was associated with reduced accumulation and possibly downregulated chemokine and inflammatory cytokine expression of the host infiltrating macrophages. Our findings demonstrate that macrophages not only act as effectors of immune injury but can be induced to provide protection against immune injury.

Target of rapamycin inhibitors (TOR-I) have a novel mode of action but uncertain clinical role. We performed a systematic review of randomized trials where immunosuppressive regimens containing TOR-I were compared with other regimens as initial therapy for kidney transplant recipients. Databases (inception, June 2005) and conference proceedings (1996–2005) were searched. Two independent reviewers assessed trials for eligibility and quality. Results at 1 year, are expressed as relative risk (RR), where values <1 favor TOR-I, or lower dose of TOR-I, and for continuous outcomes are expressed as weighted mean difference (WMD), both expressed with 95% confidence intervals (CI). Thirty-three trials (142 reports) were included (27 trials of sirolimus, 5 of everolimus, and 1 of head-to-head comparison). When TOR-I replaced calcineurin inhibitors (CNI) (8 trials with 750 participants), there was no difference in acute rejection (RR, 1.03; 95% CI, 0.74–1.44), but serum creatinine was lower (WMD, −18.31 μmol/L; 95% CI, −30.96 to −5.67) and bone marrow more suppressed (leukopenia: RR 2.02; 95% CI, 1.12–3.66; thrombocytopenia: RR, 6.97; 95% CI, 2.97–16.36; and anaemia: RR, 1.67; 95% CI, 1.27–2.20). When TOR-I replaced antimetabolites (11 trials with 3966 participants), acute rejection and cytomegalovirus infection (CMV) were reduced (RR, 0.84; 95% CI, 0.71–0.99; RR, 0.49; 95% CI, 0.37–0.65, respectively), but hypercholesterolemia was increased (RR, 1.65; 95% CI, 1.32–2.06). When low- was compared with high-dose TOR-I, with equal CNI dose (10 trials with 3,175 participants), rejection was increased (RR, 1.23; 95% CI, 1.06–1.43) but calculated glomerular filtration rate (GFR) higher (WMD, 4.27 mL/min; 95% CI, 1.12–7.41), and when lower-dose TOR-I and standard-dose CNI were compared with higher-dose TOR-I and reduced CNI, acute rejection was reduced (RR, 0.67; 95% CI, 0.52–0.88), but calculated GFR was also reduced (WMD, −9.46 mL/min; 95% CI, −12.16 to −6.76). There was no significant difference in mortality, graft loss, or malignancy risk for TOR-I in any comparison. TOR-I have been evaluated in four different primary immunosuppressive algorithms: as replacement for CNI and antimetabolites, in combination with CNI at low and high doses, and with a variable dose of CNI. Generally, surrogate endpoints for graft survival favor TOR-I (lower risk of acute rejection and higher GFR), and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression and lipid disturbance). Long-term hard-endpoint data from methodologically robust randomized trials are still required.

IL-10/TGF-β–modified macrophages, a subset of activated macrophages, produce anti-inflammatory cytokines, suggesting that they may protect against inflammation-mediated injury. Here, macrophages modified ex vivo by IL-10/TGF-β (IL-10/TGF-β Μ2) significantly attenuated renal inflammation, structural injury, and functional decline in murine adriamycin nephrosis (AN). These cells deactivated effector macrophages and inhibited CD4⁺ T cell proliferation. IL-10/TGF-β Μ2 expressed high levels of the regulatory co-stimulatory molecule B7-H4, induced regulatory T cells from CD4⁺CD25⁻ T cells in vitro, and increased the number of regulatory T cells in lymph nodes draining the kidneys in AN. The phenotype of IL-10/TGF-β Μ2 did not switch to that of effector macrophages in the inflamed kidney, and these cells did not promote fibrosis. Taken together, these data demonstrate that IL-10/TGF-β–modified macrophages effectively protect against renal injury in AN and may become part of a therapeutic strategy for chronic inflammatory disease.