Correlation of biomarkers for parasite burden and immune activation with acute kidney injury in severe falciparum malaria.

BACKGROUND: Acute kidney injury (AKI) complicating severe Plasmodium falciparum malaria occurs in up to 40% of adult patients. The case fatality rate reaches 75% in the absence of renal replacement therapy (RRT). The precise pathophysiology of AKI in falciparum malaria remains unclear. Histopathology shows acute tubular necrosis with localization of host monocytes and parasitized red blood cells in the microvasculature. This study explored the relationship of plasma soluble urokinase-type plasminogen activator receptor (suPAR), as a proxy-measure of mononuclear cell activation, and plasma P. falciparum histidine rich protein 2 (PfHRP2), as a measure of sequestered parasite burden, with AKI in severe malaria. METHODS: Admission plasma suPAR and PfHRP2 concentrations were assessed in Bangladeshi adults with severe falciparum malaria (n=137). Patients were stratified according to AKI severity based on admission creatinine clearance. RESULTS: A total of 106 (77%) patients had AKI; 32 (23%), 42 (31%) and 32 (23%) were classified into 'mild, 'moderate' and 'severe' AKI groups, respectively. Plasma suPAR and PfHRP2 concentrations increased with AKI severity (test-for-trend P <0.0001) and correlated with other markers of renal dysfunction. Admission plasma suPAR and PfHRP2 concentrations were higher in patients who later required RRT (P <0.0001 and P=0.0004, respectively). In a multivariate analysis, both increasing suPAR and PfHRP2 were independently associated with increasing urine neutrophil gelatinase-associated lipocalin concentration, a marker of acute tubular necrosis (ß=16.54 (95% CI 6.36-26.71) and ß=0.07 (0.02-0.11), respectively). CONCLUSIONS: Both sequestered parasite burden and immune activation contribute to the pathogenesis of AKI in severe falciparum malaria.

Serum levels of N-terminal proB-type natriuretic peptide in mechanically ventilated critically ill patients--relation to tidal volume size and development of acute respiratory distress syndrome.

BACKGROUND: Serum levels of N-terminal proB-type natriuretic peptide (NT-proBNP) are elevated in patients acute respiratory distress syndrome (ARDS). Recent studies showed a lower incidence of acute cor pulmonale in ARDS patients ventilated with lower tidal volumes. Consequently, serum levels of NT-proBNP may be lower in these patients. We investigated the relation between serum levels of NT-proBNP and tidal volumes in critically ill patients without ARDS at the onset of mechanical ventilation. METHODS: Secondary analysis of a randomized controlled trial of lower versus conventional tidal volumes in patients without ARDS. NT-pro BNP were measured in stored serum samples. Serial serum levels of NT-pro BNP were analyzed controlling for acute kidney injury, cumulative fluid balance and presence of brain injury. The primary outcome was the effect of tidal volume size on serum levels of NT-proBNP. Secondary outcome was the association with development of ARDS. RESULTS: Samples from 150 patients were analyzed. No relation was found between serum levels of NT-pro BNP and tidal volume size. However, NT-proBNP levels were increasing in patients who developed ARDS. In addition, higher levels were observed in patients with acute kidney injury, and in patients with a more positive cumulative fluid balance. CONCLUSION: Serum levels of NT-proBNP are independent of tidal volume size, but are increasing in patients who develop ARDS.

Systemic and urinary neutrophil gelatinase-associated lipocalins are poor predictors of acute kidney injury in unselected critically ill patients.

Background. Neutrophil gelatinase-associated lipocalin (NGAL) in serum and urine have been suggested as potential early predictive biological markers of acute kidney injury (AKI) in selected critically ill patients. Methods. We performed a secondary analysis of a multicenter prospective observational cohort study of unselected critically ill patients. Results. The analysis included 140 patients, including 57 patients who did not develop AKI, 31 patients who developed AKI, and 52 patients with AKI on admission to the ICU. Levels of sNGAL and uNGAL on non-AKI days were significantly lower compared to levels of sNGAL on RIFLE(RISK) days, RIFLE(INJURY) days, and RIFLE(FAILURE) days. The AUC of sNGAL for predicting AKI was low: 0.45 (95% confidence interval (CI) 0.27-0.63) and 0.53 (CI 0.38-0.67), 2 days and 1 day before development of AKI, respectively. The AUC of uNGAL for predicting AKI was also low: 0.48 (CI 0.33-0.62) and 0.48 (CI 0.33-0.62), 2 days and 1 day before development of AKI, respectively. AUC of sNGAL and uNGAL for the prediction of renal replacement therapy requirement was 0.47 (CI 0.37-0.58) and 0.26 (CI 0.03-0.50). Conclusions. In unselected critically ill patients, sNGAL and uNGAL are poor predictors of AKI or RRT.

Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation.

INTRODUCTION: Preclinical and clinical studies suggest that mechanical ventilation contributes to the development of acute kidney injury (AKI), particularly in the setting of lung-injurious ventilator strategies. OBJECTIVE: To determine whether ventilator settings in critically ill patients without acute lung injury (ALI) at onset of mechanical ventilation affect the development of AKI. DESIGN, SETTING, AND PATIENTS: Secondary analysis of a randomized controlled trial (N = 150), comparing conventional tidal volume (V(T), 10 mL/kg) with low tidal volume (V(T), 6 mL/kg) mechanical ventilation in critically ill patients without ALI at randomization. During the first 5 days of mechanical ventilation, the RIFLE class was determined daily, whereas neutrophil gelatinase-associated lipocalin and cystatin C levels were measured in plasma collected on days 0, 2, and 4. RESULTS: Eighty-six patients had no AKI at inclusion, and 18 patients (21%) subsequently developed AKI, but without significant difference between ventilation strategies. (Cumulative hazard, 0.26 vs 0.23; P = .88.) The courses of neutrophil gelatinase-associated lipocalin and cystatin C plasma levels did not differ significantly between randomization groups. CONCLUSION: In the present study in critically patients without ALI at onset of mechanical ventilation, lower tidal volume ventilation did not reduce the development or worsening of AKI compared with conventional tidal volume ventilation.

Laboratory prediction of the requirement for renal replacement in acute falciparum malaria.

BACKGROUND: Acute renal failure is a common complication of severe malaria in adults, and without renal replacement therapy (RRT), it carries a poor prognosis. Even when RRT is available, delaying its initiation may increase mortality. Earlier identification of patients who will need RRT may improve outcomes. METHOD: Prospectively collected data from two intervention studies in adults with severe malaria were analysed focusing on laboratory features on presentation and their association with a later requirement for RRT. In particular, laboratory indices of acute tubular necrosis (ATN) and acute kidney injury (AKI) that are used in other settings were examined. RESULTS: Data from 163 patients were available for analysis. Whether or not the patients should have received RRT (a retrospective assessment determined by three independent reviewers) was used as the reference. Forty-three (26.4%) patients met criteria for dialysis, but only 19 (44.2%) were able to receive this intervention due to the limited availability of RRT. Patients with impaired renal function on admission (creatinine clearance < 60 ml/min) (n = 84) had their laboratory indices of ATN/AKI analysed. The plasma creatinine level had the greatest area under the ROC curve (AUC): 0.83 (95% confidence interval 0.74-0.92), significantly better than the AUCs for, urinary sodium level, the urea to creatinine ratio (UCR), the fractional excretion of urea (FeUN) and the urinary neutrophil gelatinase-associated lipocalcin (NGAL) level. The AUC for plasma creatinine was also greater than the AUC for blood urea nitrogen level, the fractional excretion of sodium (FeNa), the renal failure index (RFI), the urinary osmolality, the urine to plasma creatinine ratio (UPCR) and the creatinine clearance, although the difference for these variables did not reach statistical significance. CONCLUSIONS: In adult patients with severe malaria and impaired renal function on admission, none of the evaluated laboratory indices was superior to the plasma creatinine level when used to predict a later requirement for renal replacement therapy.

Serum and urine cystatin C are poor biomarkers for acute kidney injury and renal replacement therapy.

PURPOSE: To evaluate whether cystatin C in serum (sCyC) and urine (uCyC) can predict early acute kidney injury (AKI) in a mixed heterogeneous intensive care unit (ICU), and also whether these biomarkers can predict the need for renal replacement therapy (RRT). METHODS: Multicenter prospective observational cohort study in patients ≥18 years old and with expected ICU stay ≥72 h. The RIFLE class for AKI was calculated daily, while sCyC and uCyC were determined on days 0, 1, and alternate days until ICU discharge. Test characteristics were calculated to assess the diagnostic performance of CyC. RESULTS: One hundred fifty-one patients were studied, and three groups were defined: group 0 (N = 60), non-AKI; group 1 (N = 35), AKI after admission; and group 2 (N = 56), AKI at admission. We compared the two days prior to developing AKI from group 1 with the first two study days from group 0. On Day -2, median sCyC was significantly higher (0.93 versus 0.80 mg/L, P = 0.01), but not on Day -1 (0.98 versus 0.86 mg/L, P = 0.08). The diagnostic performance for sCyC was fair on Day -2 [area under the curve (AUC) 0.72] and poor on Day -1 (AUC 0.62). Urinary CyC had no diagnostic value on either of the two days prior to AKI (AUC <0.50). RRT was started in 14 patients with AKI; sCyC and uCyC determined on Day 0 were poor predictors for the need for RRT (AUC ≤0.66). CONCLUSIONS: In this study, sCyC and uCyC were poor biomarkers for prediction of AKI and the need for RRT.

Plasma levels of surfactant protein D and KL-6 for evaluation of lung injury in critically ill mechanically ventilated patients.

BACKGROUND: Preventing ventilator-associated lung injury (VALI) has become pivotal in mechanical ventilation of patients with acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome (ARDS). In the present study we investigated whether plasma levels of lung-specific biological markers can be used to evaluate lung injury in patients with ALI/ARDS and patients without lung injury at onset of mechanical ventilation. METHODS: Plasma levels of surfactant protein D (SP-D), Clara Cell protein (CC16), KL-6 and soluble receptor for advanced glycation end-products (sRAGE) were measured in plasma samples obtained from 36 patients - 16 patients who were intubated and mechanically ventilated because of ALI/ARDS and 20 patients without lung injury at the onset of mechanical ventilation and during conduct of the study. Patients were ventilated with either a lung-protective strategy using lower tidal volumes or a potentially injurious strategy using conventional tidal volumes. Levels of biological markers were measured retrospectively at baseline and after 2 days of mechanical ventilation. RESULTS: Plasma levels of CC16 and KL-6 were higher in ALI/ARDS patients at baseline as compared to patients without lung injury. SP-D and sRAGE levels were not significantly different between these patients. In ALI/ARDS patients, SP-D and KL-6 levels increased over time, which was attenuated by lung-protective mechanical ventilation using lower tidal volumes (P = 0.02 for both biological markers). In these patients, with either ventilation strategy no changes over time were observed for plasma levels of CC16 and sRAGE. In patients without lung injury, no changes of plasma levels of any of the measured biological markers were observed. CONCLUSION: Plasma levels of SP-D and KL-6 rise with potentially injurious ventilator settings, and thus may serve as biological markers of VALI in patients with ALI/ARDS.

Serum cystatin C-A useful endogenous marker of renal function in intensive care unit patients at risk for or with acute renal failure?

Critically ill patients are at high risk for developing acute renal failure (ARF). The prevention of ARF is of outmost importance in order to improve the increased morbidity and mortality associated with ARF. Unfortunately, there is lack of adequate endogenous markers that can identify renal dysfunction early - this hampers timely application of measures to prevent further renal damage. The use of exogenous markers of renal function is not only time-consuming but also expensive, and therefore can not be used on a regular basis in the intensive care unit. Both the presently used endogenous and exogenous markers are not reliable during continuous renal replacement therapy (CRRT) because these markers are removed by the therapy itself impeding early detection of recovering of renal function. Cystatin C has been proposed as an alternative endogenous marker of renal function for more than 15 years. In this manuscript we review the literature on the role of cystatin C as marker for renal function, focusing on the critically ill patient. Serum cystatin C concentrations have been found to relate to renal impairment and suggest that cystatin C is more sensitive to detect mild decreases in GFR. Cystatin C could be an important tool both to recognize early renal dysfunction and to identify renal recovery while on CRRT in the critically ill patient, however, we are in need of more studies.