Levels of protein C and soluble thrombomodulin in critically ill patients with acute kidney injury: a multicenter prospective observational study.

Endothelial dysfunction contributes to the development of acute kidney injury (AKI) in animal models of ischemia reperfusion injury and sepsis. There are limited data on markers of endothelial dysfunction in human AKI. We hypothesized that Protein C (PC) and soluble thrombomodulin (sTM) levels could predict AKI. We conducted a multicenter prospective study in 80 patients to assess the relationship of PC and sTM levels to AKI, defined by the AKIN creatinine (AKI Scr) and urine output criteria (AKI UO). We measured marker levels for up to 10 days from intensive care unit admission. We used area under the curve (AUC) and time-dependent multivariable Cox proportional hazard model to predict AKI and logistic regression to predict mortality/non-renal recovery. Protein C and sTM were not different in patients with AKI UO only versus no AKI. On intensive care unit admission, as PC levels are usually lower with AKI Scr, the AUC to predict the absence of AKI was 0.63 (95%CI 0.44-0.78). The AUC using log10 sTM levels to predict AKI was 0.77 (95%CI 0.62-0.89), which predicted AKI Scr better than serum and urine neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, urine kidney injury molecule-1 and liver-fatty acid-binding protein. In multivariable models, PC and urine NGAL levels independently predicted AKI (p=0.04 and 0.02) and PC levels independently predicted mortality/non-renal recovery (p=0.04). In our study, PC and sTM levels can predict AKI Scr but are not modified during AKI UO alone. PC levels could independently predict mortality/non-renal recovery. Additional larger studies are needed to define the relationship between markers of endothelial dysfunction and AKI

Standard versus High-Dose CVVHDF for ICU-Related Acute Renal Failure

The effect of dosage of continuous venovenous hemodiafiltration (CVVHDF) on survival in patients with acute renal failure (ARF) is unknown. In this study, 200 critically ill patients with ARF were randomly assigned to receive CVVHDF with prefilter replacement fluid at an effluent rate of either 35 ml/kg per h (high dosage) or 20 ml/kg per h (standard dosage). The primary study outcome, survival to the earlier of either intensive care unit discharge or 30 d, was 49% in the high-dosage arm and 56% in the standard-dosage arm (odds ratio 0.75; 95% confidence interval 0.43 to 1.32; P = 0.32). Among hospital survivors, 69% of those in the high-dosage arm recovered renal function compared with 80% of those in the standard-dosage arm (P = 0.29); therefore, a difference in patient survival or renal recovery was not detected between patients receiving high-dosage or standard-dosage CVVHDF

Characteristics of the study patients at intensive care unit admission.

<p>AKI: acute kidney injury; ICU: intensive care unit; CKD: chronic kidney disease; eGFR: estimated glomerular filtration rate; CHF: cardiac heart failure; BUN: blood urea nitrogen; SOFA: Sequential Organ Failure Assessment; APACHE: Acute Physiology and Chronic Health Evaluation</p><p>AKI according to serum creatinine is defined as an increase in serum creatinine level of more than 27 μmol/l or more than 50% from a reference creatinine within 48 hours with or without urine output less than 0.5 ml/kg/hour for at least 6 hours (AKIN criteria)</p><p>AKI according to urine output alone was defined as urine output less than 0.5 ml/kg/hour for at least 6 hours without significant changes in serum creatinine</p><p>No AKI was defined as no significant changes in serum creatinine or urine output</p><p>*to convert from μmol/l to mg/dl, divide by 88.4</p><p>**to convert from mmol/l to mg/dl, multiply by 2.81</p><p>Characteristics of the study patients at intensive care unit admission.</p

Area under the curves of kidney biomarkers to predict acute kidney injury.

<p>AKI Scr is defined as the AKIN serum creatinine criterion</p><p>Area under the curves of kidney biomarkers to predict acute kidney injury.</p

Outcomes of the study patients.

<p>*absence of renal recovery defined as a difference between creatinine at hospital discharge and reference creatinine >27 μmol/l in survivors</p><p>Outcomes of the study patients.</p

a and b.

<p>Median soluble thrombomodulin and Protein C values over the first three days according to AKIN diagnosis criteria. Soluble thrombomodulin: AKI Scr: 3.06 ng/ml (IQR 1.69–10.2 ng/ml), AKI based on urine output alone (UO): 1.35 ng/ml (IQR 0.36–2.47 ng/ml), No AKI: 0.42 ng/ml (IQR 0.22–2.39 ng/ml), Significant differences between categories: p<0.001, No acute kidney injury (AKI) (n = 24) vs AKI UO alone (n = 38) p = 0.84, No AKI (n = 24) vs AKI serum creatinine (SCr) (n = 18) p<0.0001, AKI UO alone (n = 38) vs AKI SCr (n = 18) p<0.0001. Protein C (p = 0.15): AKI Scr: 83.0% (IQR 50.0–118.0%), AKI UO alone: 87.0% (IQR 72.3–103.0%), No AKI: 92.5% (IQR 72.3–117.8%).</p

a and b.

<p>Screening, enrollment procedures and follow-up of study patients. AKI: acute kidney injury, AKI Scr: acute kidney injury based on serum creatinine criterion, CKD: chronic kidney disease, Hb: hemoglobin, Ht: hematocrit, ICU: intensive care unit. Reasons for exclusion can include more than 1 criterion.</p

Levels of Protein C and Soluble Thrombomodulin in Critically Ill Patients with Acute Kidney Injury: A Multicenter Prospective Observational Study

Endothelial dysfunction contributes to the development of acute kidney injury (AKI) in animal models of ischemia reperfusion injury and sepsis. There are limited data on markers of endothelial dysfunction in human AKI. We hypothesized that Protein C (PC) and soluble thrombomodulin (sTM) levels could predict AKI. We conducted a multicenter prospective study in 80 patients to assess the relationship of PC and sTM levels to AKI, defined by the AKIN creatinine (AKI Scr) and urine output criteria (AKI UO). We measured marker levels for up to 10 days from intensive care unit admission. We used area under the curve (AUC) and time-dependent multivariable Cox proportional hazard model to predict AKI and logistic regression to predict mortality/non-renal recovery. Protein C and sTM were not different in patients with AKI UO only versus no AKI. On intensive care unit admission, as PC levels are usually lower with AKI Scr, the AUC to predict the absence of AKI was 0.63 (95%CI 0.44-0.78). The AUC using log10 sTM levels to predict AKI was 0.77 (95%CI 0.62-0.89), which predicted AKI Scr better than serum and urine neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C, urine kidney injury molecule-1 and liver-fatty acid-binding protein. In multivariable models, PC and urine NGAL levels independently predicted AKI (p=0.04 and 0.02) and PC levels independently predicted mortality/non-renal recovery (p=0.04). In our study, PC and sTM levels can predict AKI Scr but are not modified during AKI UO alone. PC levels could independently predict mortality/non-renal recovery. Additional larger studies are needed to define the relationship between markers of endothelial dysfunction and AKI