Near-drowning: new perspectives for human hypoxic acute kidney injury.

Concepts regarding hypoxic acute kidney injury (AKI) are derived from widely used warm ischemia-reflow (WIR) models, characterized by extensive proximal tubular injury and associated with profound inflammation. However, there is ample clinical and experimental data indicating that hypoxic AKI may develop without total cessation of renal blood flow, with a different injury pattern that principally affects medullary thick limbs in the outer medulla. This injury pattern likely reflects an imbalance between blood and oxygen supply and oxygen expenditure, principally for tubular transport. Experimental models of hypoxic AKI other than WIR are based on mismatched oxygen delivery and consumption, particularly within the physiologically hypoxic outer medulla. However, evidence for such circumstances in human AKI is lacking. Recent analysis of the clinical course and laboratory findings of patients following near-drowning (ND) provides a rare glimpse into such a scenario. This observation supports the role of renal hypoxia in the evolution of AKI, as renal impairment could be predicted by the degree of whole-body hypoxia (reflected by lactic acidosis). Furthermore, there was a close association of renal functional impairment with indices of reduced oxygen delivery (respiratory failure and features of intense sympathetic activity) and of enhanced oxygen consumption for active tubular transport (extrapolated from the calculated volume of consumed hypertonic seawater). This unique study in humans supports the concept of renal oxygenation imbalance in hypoxic AKI. The drowning scenario, particularly in seawater, may serve as an archetype of this disorder, resulting from reduced oxygen delivery, combined with intensified oxygen consumption for tubular transport.

Role of Hypoxia in Renal Failure Caused by Nephrotoxins and Hypertonic Solutions.

Hypoxia plays a role in the pathogenesis of acute kidney injury under diverse clinical settings, including nephrotoxicity. Although some nephrotoxins exert direct renal parenchymal injury, likely with consequent altered oxygenation, others primarily reduce renal parenchymal oxygenation, leading to hypoxic tubular damage. As outlined in this review, nephrotoxin-related renal hypoxia may result from an altered renal oxygen supply (cyclosporine), enhanced oxygen consumption for tubular transport (agents inducing osmotic diuresis), or their combination (nonsteroidal anti-inflammatory drugs, radiocontrast agents, and others). Most agents causing hypoxic renal injury further supress physiologic low medullary Po2, in which a limited regional blood supply barely matches the intense regional tubular transport and oxygen consumption. The medullary tubular transport and blood supply are finely matched, securing oxygen sufficiency. Predisposition to hypoxia-mediated nephrotoxicity by medical conditions, such as chronic kidney disease or diabetes, may be explained by malfunctioning of control systems that normally maintain medullary oxygenation. However, this propensity may be diminished by hypoxia-mediated adaptive responses governed by hypoxia-inducible factors. Recent reports have suggested that inhibitors of sodium-glucose cotransporters and the administration of hypertonic saline may be added to the growing list of common therapeutic interventions that intensify medullary hypoxia, and potentially could lead to hypoxic acute kidney injury.

The association between fluconazole dose and MIC with mortality and persistence in candidemia.

To evaluate the association between fluconazole exposure parameters and clinical outcomes in patients with candidemia. We retrospectively included all adults with candidemia in a single center from January 2009 to December 2017, treated initially with fluconazole for fluconazole-susceptible candidemia. We assessed the association between fluconazole exposure parameters and 30-day mortality or 14-day clinical failure, a composite of mortality at day 14 or persistent candidemia ≥ 72 h, in all patients and in patients with C. glabrata candidemia. During the study period, 158 patients fulfilled the inclusion criteria. Main species were C. albicans 66 (41.8%), C. glabrata 35 (22.2%), and C. parapsilosis 31 (19.6%). Sixty patients (38%) died within 30 days. Sixty-one patients (38.6%) experienced 14-day failure. In 30-day survivors, the median AUC24/MIC was 2279 [398, 5989] versus 1764 [238, 6714] h in non-survivors, p = 0.75. Median fluconazole MIC was 0.75 [0.25, 4] and 1 [0.22, 5.50] mg/L, p = 0.54, respectively. Similar non-significant differences were found for other fluconazole exposure parameters and in the 14-day clinical failure analysis. For C. glabrata, a higher AUC24/MIC was observed among 30-day survivors with a median of 230 [77, 539] compared to 96 [75, 164] h in non-survivors, p = 0.008, in parallel with a trend for lower MIC values (median 7 [1, 2] versus 16 [8, 24] mg/L, p = 0.06, respectively). Currently used fluconazole dosing has no association with clinical outcome in Candida with low MIC values. For Candida species with high MICs, attention to dosing is needed.

Risk Factors for Non-Albicans Candidemia Focusing on Prior Antifungal and Immunosuppressive Therapy.

BACKGROUND: With the widespread use of antifungal agents, the frequency of non-albicans Candida (NAC) blood-stream infections (BSI) is increasing. OBJECTIVES: To describe the epidemiology, clinical manifestations, and risk factors for NAC BSI, focusing on prior antifungal and immunosuppressive therapy. METHODS: The authors conducted an observational, retrospective cohort study among adult patients with candidemia at the Rambam Health Care Campus, a tertiary medical center in Israel, between 2009 and 2015. Comparisons between patients with Candidemia albicans and NAC candidemia were performed. Regression analysis, with NAC BSI as the dependent variable and significant risk factors for NAC as independent variables, was performed. RESULTS: A total of 308 episodes of candidemia were included. C. albicans was isolated in 30.8% of patients (95/308), while NAC spp. were isolated in the rest. Significant independent risk factors for NAC included immunosuppression therapy (odds ratio [OR] 0.38, 95% confidence interval [95%CI] 0.19-0.76) and previous azole use (OR 0.2, 95%CI 0.06-0.710). The interaction between prior azole and immunosuppression therapy in the model was not significant, and after its inclusion in the model only immunosuppression remained significantly associated with NAC. In the subgroup of patients who did not receive prior azoles, immunosuppression therapy, neutropenia, and bone marrow transplantation were significantly associated with NAC. CONCLUSIONS: Independent of previous azole treatment, immunosuppressive therapy was a significant risk factor for NAC in our cohort.

The association between treatment appropriateness according to EUCAST and CLSI breakpoints and mortality among patients with candidemia: a retrospective observational study.

To evaluate the association between appropriate antifungal treatment and mortality among patients with candidemia using different breakpoint definitions. In a retrospective study, we included all adults with candidemia in a tertiary center between 2009 and 2015. We defined three versions of appropriate (covering) antifungal treatment, according to Clinical and Laboratory Standards Institute (CLSI) 2008, CLSI 2012, and European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2017 update) breakpoints. For empiric treatment, we evaluated the association with 30-day mortality. For definitive treatment, we evaluated the association with 90-day mortality among patients surviving the first week after candidemia onset. Adjusted odds ratios (OR) from a bivariate logistic regression with 95% confidence intervals are reported. We identified 302 patients with 308 separate candidemia episodes. The crude 30-day mortality was 55% (168/308). Resistance to anidulafungin increased from 3.5 to 51.6% and to fluconazole from 15.2 to 44.1%, when applying CLSI 2008 and EUCAST definitions, respectively. Appropriate empirical treatment was significantly associated with lower 30-day mortality using the CLSI 2008 definitions, adjusted OR 0.56 (0.33-0.96). The associations were similar, though not statistically significant for EUCAST, 0.58 (0.33-1.00), and CLSI 2012, OR 0.62 (0.37-1.04). Appropriate definitive treatment according to CLSI 2012 and EUCAST was independently associated with lower 90-day mortality, ORs 0.31 (0.13-0.75) and 0.44 (0.23-0.8), respectively. With CLSI 2008, the association was similar but not statistically significant, OR 0.4 (0.11-1.41), with few isolates classified as resistant. Considering the major shift in resistance prevalence when applying CLSI 2008, CLSI 2012, and EUCAST breakpoint definitions, no major differences were observed in their association with mortality.