Predictive Value of Plasma NGAL:Hepcidin-25 for Major Adverse Kidney Events After Cardiac Surgery with Cardiopulmonary Bypass: A Pilot Study

Background@#Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 are involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We explored the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events (MAKE) after cardiac surgery. @*Methods@#We compared the predictive value of plasma NGAL, hepcidin-25, and plasma NGAL:hepcidin-25 with that of serum creatinine (Cr) and urinary output and protein for primary-endpoint MAKE (acute kidney injury [AKI] stages 2 and 3, persistent AKI > 48 hours, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses. @*Results@#At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, plasma interleukin-6, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77, 0.79, 0.74, and 0.74, respectively) and AKI (0.73, 0.89, 0.70, and 0.69). For AKI prediction, plasma NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00–0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC < 0.70). Only plasma NGAL:hepcidin-25 correctly reclassified patients according to their MAKE and AKI status (category-free net reclassification improvement: 0.82 [95% CI 0.12–1.52], 1.03 [0.29–1.77]). After adjustment to the Cleveland risk score, plasma NGAL:hepcidin-25 ≥ 0.9 independently predicted MAKE (adjusted odds ratio 16.34 [95% CI 1.77–150.49], P = 0.014). @*Conclusions@#Plasma NGAL:hepcidin-25 is a promising marker for predicting postoperative MAKE.

A Stabilizing Agent, PCA/DTPA, Improves Plasma Storage Life for the Chromsystems Vitamin C Assay up to Six Months

The commonly used Chromsystems vitamin C (ascorbate) assay (Munich, Germany) has a sample storage life of five days at –20°C. Stabilizing agents have been successfully used to increase longevity; however, their suitability with this commercial assay is unclear. We investigated the compatibility of a stabilizing agent, perchloric acid/diethylenetriaminepentaacetic acid (PCA/DTPA), with the Chromsystems assay. Plasma was stored at –80°C, with or without PCA/DTPA. Storage up to six months was assessed through baseline and repeat analyses, stability was assessed by comparing paired non-stabilized and PCA/ DTPA-stabilized plasma, and performance was assessed using allowable performance specifications of an external quality assurance program. Ascorbate concentration was significantly lower in non-stabilized plasma than in paired PCA/DTPA-stabilized plasma, with a proportional difference of 11% (P = 0.01). All storage analysis results were within the allowable performance specifications. Storage at –80°C prevented plasma ascorbate oxidation; however, substantial oxidation occurred during sample processing. In conclusion, PCA/DTPA significantly reduces ascorbate oxidation, and PCA/DTPA-stabilized ascorbate plasma is compatible with the Chromsystems assay and stable for up to six months, when stored at –80°C.

Urinary Biomarkers may Complement the Cleveland Score for Prediction of Adverse Kidney Events After Cardiac Surgery: A Pilot Study

BACKGROUND: The ability of urinary biomarkers to complement established clinical risk prediction models for postoperative adverse kidney events is unclear. We assessed the effect of urinary biomarkers linked to suspected pathogenesis of cardiac surgery-induced acute kidney injury (AKI) on the performance of the Cleveland Score, a risk assessment model for postoperative adverse kidney events. METHODS: This pilot study included 100 patients who underwent open-heart surgery. We determined improvements to the Cleveland Score when adding urinary biomarkers measured using clinical laboratory platforms (neutrophil gelatinase-associated lipocalin [NGAL], interleukin-6) and those in the preclinical stage (hepcidin-25, midkine, alpha-1 microglobulin), all sampled immediately post-surgery. The primary endpoint was major adverse kidney events (MAKE), and the secondary endpoint was AKI. We performed ROC curve analysis, assessed baseline model performance (odds ratios [OR], 95% CI), and carried out statistical reclassification analyses to assess model improvement. RESULTS: NGAL (OR [95% CI] per 20 concentration-units wherever applicable): (1.07 [1.01–1.14]), Interleukin-6 (1.51 [1.01–2.26]), midkine (1.01 [1.00–1.02]), 1-hepcidin-25 (1.08 [1.00–1.17]), and NGAL/hepcidin-ratio (2.91 [1.30–6.49]) were independent predictors of MAKE and AKI (1.38 [1.03–1.85], 1.08 [1.01–1.15], 1.01 [1.00–1.02], 1.09 [1.01–1.18], and 3.45 [1.54–7.72]). Category-free net reclassification improvement identified interleukin-6 as a model-improving biomarker for MAKE and NGAL for AKI. However, only NGAL/hepcidin-25 improved model performance for event- and event-free patients for MAKE and AKI. CONCLUSIONS: NGAL and interleukin-6 measured immediately post cardiac surgery may complement the Cleveland Score. The combination of biomarkers with hepcidin-25 may further improve diagnostic discrimination.

The Role of Oliguria and the Absence of Fluid Administration and Balance Information in Illness Severity Scores / 대한중환자의학회지

Urinary examination has formed part of patient assessment since the earliest days of medicine. Current definitions of oliguria are essentially arbitrary, but duration and intensity of oliguria have been associated with an increased risk of mortality, and this risk is not completely attributable to the development of concomitant acute kidney injury (AKI) as defined by changes in serum creatinine concentration. The increased risk of death associated with the development of AKI itself may be modified by directly or indirectly by progressive fluid accumulation, due to reduced elimination and increased fluid administration. None of the currently extant major illness severity scoring systems or outcome prediction models use modern definitions of AKI or oliguria, or any values representative of fluid volumes variables. Even if a direct relationship with mortality is not observed, then it is possible that fluid balance or fluid volume variables mediate the relationship between illness severity and mortality in the renal and respiratory physiological domains. Fluid administration and fluid balance may then be an important, easily modifiable therapeutic target for future investigation. These relationships require exploration in large datasets before being prospectively validated in groups of critically ill patients from differing jurisdictions to improve prognostication and mortality prediction.

The Role of Oliguria and the Absence of Fluid Administration and Balance Information in Illness Severity Scores / 대한구급학회지

Urinary examination has formed part of patient assessment since the earliest days of medicine. Current definitions of oliguria are essentially arbitrary, but duration and intensity of oliguria have been associated with an increased risk of mortality, and this risk is not completely attributable to the development of concomitant acute kidney injury (AKI) as defined by changes in serum creatinine concentration. The increased risk of death associated with the development of AKI itself may be modified by directly or indirectly by progressive fluid accumulation, due to reduced elimination and increased fluid administration. None of the currently extant major illness severity scoring systems or outcome prediction models use modern definitions of AKI or oliguria, or any values representative of fluid volumes variables. Even if a direct relationship with mortality is not observed, then it is possible that fluid balance or fluid volume variables mediate the relationship between illness severity and mortality in the renal and respiratory physiological domains. Fluid administration and fluid balance may then be an important, easily modifiable therapeutic target for future investigation. These relationships require exploration in large datasets before being prospectively validated in groups of critically ill patients from differing jurisdictions to improve prognostication and mortality prediction.

The Complexities of Intravenous Fluid Research: Questions of Scale, Volume, and Accumulation / 대한중환자의학회지

Despite near ubiquity, information regarding fluids consumption at a health care systems level, and patient exposure at an individual level, is surprisingly limited in the medical literature. The epidemiology of the foundational medical intervention of intravenous fluid administration is incredibly complex, with millions of patients being exposed internationally every year. Fluid is being given for different reasons, to different targets, following different triggers, by different specialties in different countries, and any observations that can be made are thought to have limited external validity to other jurisdictions and patient groups. The independent effects of fluid administration and fluid accumulation are very hard to separate from other markers of illness severity and aspects of the process of care. Fluid accumulation can result in organ injury, even when the fluid is being given to purportedly ameliorate or prevent such injury, and if it were independently associated with mortality then would be an easily accessible and modifiable risk factor for subsequent morbidity or death. Despite their ubiquity, it is clear that we have limited understanding of the effects of the intravenous fluids we use daily in the most vulnerable of patient groups. The research agenda in this field is large and urgent.

The Complexities of Intravenous Fluid Research: Questions of Scale, Volume, and Accumulation / 대한구급학회지

Despite near ubiquity, information regarding fluids consumption at a health care systems level, and patient exposure at an individual level, is surprisingly limited in the medical literature. The epidemiology of the foundational medical intervention of intravenous fluid administration is incredibly complex, with millions of patients being exposed internationally every year. Fluid is being given for different reasons, to different targets, following different triggers, by different specialties in different countries, and any observations that can be made are thought to have limited external validity to other jurisdictions and patient groups. The independent effects of fluid administration and fluid accumulation are very hard to separate from other markers of illness severity and aspects of the process of care. Fluid accumulation can result in organ injury, even when the fluid is being given to purportedly ameliorate or prevent such injury, and if it were independently associated with mortality then would be an easily accessible and modifiable risk factor for subsequent morbidity or death. Despite their ubiquity, it is clear that we have limited understanding of the effects of the intravenous fluids we use daily in the most vulnerable of patient groups. The research agenda in this field is large and urgent.