A panel of urine-derived biomarkers to identify sepsis and distinguish it from systemic inflammatory response syndrome.

Sepsis is a potentially fatal condition caused by infection. It is frequently difficult to distinguish sepsis from systemic inflammatory response syndrome (SIRS), often resulting in poor prognoses and the misuse of antibiotics. Hence, highly sensitive and specific biomarkers are needed to differentiate sepsis from SIRS. Urine samples were collected and segregated by group (a sepsis group, a SIRS group, and a healthy control group). iTRAQ was used to identify the differentially expressed proteins among the three groups. The identified proteins were measured by ELISA in urine samples. Finally, all the acquired data were analyzed in SPSS. C-reactive protein, leucine-rich alpha glycoprotein-1 and serum amyloid A (SAA) protein were differentially expressed among the three groups. The adjusted median concentrations of urinary C-reactive protein were 1337.6, 358.7, and 2.4 in the sepsis, SIRS, and healthy control groups, respectively. The urinary leucine-rich alpha glycoprotein-1 levels in these three groups were 1614.4, 644.5, and 13.6, respectively, and the levels of SAA were 6.3, 2.9, and 0.07, respectively. For all three of these measures, the sepsis group had higher levels than the SIRS group (P < 0.001), and the SIRS group had higher levels than the healthy control group. When combined, the three biomarkers had a sensitivity of 0.906 and a specificity of 0.896 in distinguishing sepsis from SIRS. Urinary C-reactive protein, urinary leucine-rich alpha glycoprotein-1 and urinary SAA have diagnostic value in cases of sepsis. This initial study suggests the possibility of improved differential diagnosis between sepsis and systemic inflammatory response syndrome; additional confirmation is necessary to corroborate the findings.

Remote ischaemic preconditioning does not modulate the systemic inflammatory response or renal tubular stress biomarkers after endotoxaemia in healthy human volunteers: a single-centre, mechanistic, randomised controlled trial.

BACKGROUND: Remote ischaemic preconditioning (RIPC) consists of repeated cycles of limb ischaemia and reperfusion, which may reduce perioperative myocardial ischaemic damage and kidney injury. We hypothesised that RIPC may be beneficial by attenuating the systemic inflammatory response. We investigated whether RIPC affects the response in humans to bacterial endotoxin (lipopolysaccharide [LPS]) by measuring plasma cytokines and renal cell-cycle arrest mediators, which reflect renal tubular stress. METHODS: Healthy male volunteers were randomised to receive either daily RIPC for 6 consecutive days (RIPCmultiple, n=10) plus RIPC during the 40 min preceding i.v. LPS (2 ng kg-1), RIPC only during the 40 min before LPS (RIPCsingle, n=10), or no RIPC preceding LPS (control, n=10). As a surrogate marker of renal tubular stress, the product of urinary concentrations of two cell-cycle arrest markers was calculated (tissue inhibitor of metalloproteinases-2 [TIMP2]*insulin-like growth factor binding protein-7 [IGFBP7]). Data are presented as median (inter-quartile range). RESULTS: In both RIPC groups, RIPC alone increased [TIMP2]*[IGFBP7]. LPS administration resulted in fever, flu-like symptoms, and haemodynamic alterations. Plasma cytokine concentrations increased profoundly during endotoxaemia (control group: tumor necrosis factor alpha [TNF-α] from 14 [9-16] pg ml-1 at baseline to 480 [284-709] pg ml-1 at 1.5 h after LPS; interleukin-6 [IL-6] from 4 [4-4] pg ml-1 at baseline to 659 [505-1018] pg ml-1 at 2 h after LPS). LPS administration also increased urinary [TIMP2[*[IGFBP7]. RIPC had no effect on LPS-induced cytokine release or [TIMP2]*[IGFBP7]. CONCLUSIONS: RIPC neither modulated systemic cytokine release nor attenuated inflammation-induced tubular stress after LPS. However, RIPC alone induced renal markers of cell-cycle arrest. CLINICAL TRIAL REGISTRATION: NCT02602977.

The Predictive Value of Preoperative High-Sensitive C-Reactive Protein/Albumin Ratio in Systemic Inflammatory Response Syndrome After Percutaneous Nephrolithotomy.

OBJECTIVE: The aim of the study was to evaluate the predictive value of preoperative high-sensitive C-reactive protein/albumin (hs-CRP/Alb) ratio in systemic inflammatory response syndrome (SIRS) after percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: We retrospectively reviewed 556 patients who underwent PCNL at our institution between August 2015 and February 2018. The primary endpoint for the study was the development of SIRS after operation. A univariate and multivariate logistic regression analysis was used to identify the independent factors associated with the post-PCNL SIRS. Receiver operating characteristic (ROC) curves were constructed and the areas under the curve (AUC) were calculated to compare the discriminatory ability of systemic inflammation biomarkers. RESULTS: Among the 556 patients who underwent PCNL, 123 patients (22.1%) developed SIRS. Multivariate analysis revealed that female gender (OR 1.691; 95% CI 1.045-2.735; p = 0.032), positive urine culture (OR 1.972; 95% CI 1.204-3.231; p < 0.01), hs-CRP/Alb ratio (OR 6.925; 95% CI 4.244-11.300; p < 0.01), neutrophil to lymphocyte ratio (NLR) (OR 2.476; 95% CI 1.471-4.167; p < 0.01), and prognostic nutritional index (PNI) (OR 0.559; 95% CI 0.338-0.924; p = 0.023) were independent predictors of post-PCNL SIRS. The optimal cutoff value of the hs-CRP/Alb ratio was 0.06 from the ROC analysis. The elevated hs-CRP/Alb ratio was significantly associated with female gender, positive urine culture, hs-CRP, albumin, leukocyte, neutrophil, monocyte, platelet, hemoglobin, creatinine, NLR, lymphocyte to monocyte ratio (LMR), platelet to lymphocyte ratio (PLR), PNI, high-sensitive modified Glasgow prognostic score (hs-mGPS), development of sepsis, ICU admission, and length of stay (all p < 0.05). In addition, the hs-CRP/Alb ratio had a higher AUC (0.791) with a sensitivity of 76.4% and a specificity of 73.2% than NLR (0.669), LMR (0.633), PLR (0.594), PNI (0.629), and hs-mGPS (0.739). CONCLUSIONS: The preoperative hs-CRP/Alb ratio is independently predictive for the development of SIRS after PCNL. Moreover, compared with other systemic inflammation biomarkers, the preoperative hs-CRP/Alb ratio shows a better predictive value.

Mitochondrial DNA is Released in Urine of SIRS Patients With Acute Kidney Injury and Correlates With Severity of Renal Dysfunction.

Systemic inflammatory response syndrome (SIRS) is characterized by the activation of the innate immune system resulting in stimulation of inflammatory responses, coagulation, and platelet activation that may contribute to complication such as the development of acute kidney injury (AKI). AKI importantly worsens the outcome of SIRS, implying the existence of a detrimental cross talk via systemic messages. Mitochondria are a source of damage-associated molecular patterns (DAMPs) and are thought to form a molecular link between tissue injury and stimulation of innate immunity. The role of mitochondrial DNA (mtDNA) in the cross talk between the onset of SIRS and subsequent development of AKI is unknown. Hence, we performed a case control study in critically ill patients with SIRS diagnosed with or without AKI, in which we determined mtDNA levels in plasma and urine, and correlated these to markers of renal impairment, inflammation, coagulation, and platelet activation. In addition, we exposed mice, primary renal tubular epithelial cells (TECs), and platelets to mtDNA or purified mitochondrial ligands, and measured their response to elucidate underlying pathophysiological mechanisms. Our data reveal that increased systemic mtDNA levels in SIRS patients do not correlate with systemic inflammation and renal disease activity. Moreover, AKI does not have an additional effect on circulating mtDNA levels. In contrast, we found that urinary mtDNA levels correlate with an elevated albumin creatinine ratio (ACR) as well as with increased urinary markers of inflammation, coagulation, and platelet activation. Both renal TECs and platelets respond to mtDNA and mtDNA ligands, leading to increased expression of, respectively, inflammatory cytokines and P-selectin. Moreover, activation of platelets results in mtDNA release. Together, these data suggest that circulating mtDNA is probably not important in the detrimental cross talk between SIRS and AKI, whereas renal mtDNA accumulation may be related to intrarenal inflammation, coagulation processes, and renal dysfunction in the pathophysiology of SIRS.

The importance of microalbuminuria in predicting patient outcome in a PICU.

OBJECTIVE: To evaluate the prognostic significance of microalbuminuria in critically ill children. DESIGN: Prospective study. SETTING: PICU of a teaching hospital. PATIENTS: Admitted critically ill children. INTERVENTIONS: The urine albumin-creatinine ratio was measured at admission and at 24 hours. Pediatric Risk of Mortality, Pediatric Index of Mortality II, Pediatric Logistic Organ Dysfunction, and Inotrope Score were calculated. MEASUREMENTS AND MAIN RESULTS: In total, 102 patients (median age, 19 mo) were included in the study, among whom were 30 mortalities. Microalbuminuria was identified in 62 patients (64%). The patients were classified into three groups: patients with sepsis, patients with noninfectious systemic inflammatory response syndrome, and patients without systemic inflammatory response syndrome. The highest clinical scores, albumin-creatinine ratio levels, mortality rate, and duration of mechanical ventilation were found in the sepsis group, and the lowest values were seen in patients without systemic inflammatory response syndrome (p < 0.05). Significant correlations were observed between the albumin-creatinine ratio levels and the clinical scores (p < 0.05). The receiver operating characteristics curve analysis showed that the areas under the curves were 0.818 and 0.781, respectively, for albumin-creatinine ratio measured at admission and at 24 hours to identify PICU mortality. At a cutoff value of 34.2 mg/g, albumin-creatinine ratio measured at admission may be able to discriminate between patients a with sensitivity of 63.3%, specificity of 93.3%, positive predictive value of 95%, and negative predictive value of 56%. CONCLUSIONS: Microalbuminuria is a simple, inexpensive, and useful tool for predicting mortality and morbidity in critically ill children in the PICU.

Diagnostic value of urine sCD163 levels for sepsis and relevant acute kidney injury: a prospective study.

BACKGROUND: Sepsis is a common syndrome in critically ill patients and easily leads to the occurrence of acute kidney injury (AKI), with high mortality rates. This study aimed to investigate the diagnostic value of urine soluble CD163 (sCD163) for identification of sepsis, severity of sepsis, and for secondary AKI, and to assess the patients' prognosis. METHODS: We enrolled 20 cases with systemic inflammatory response syndrome (SIRS), 40 cases with sepsis (further divided into 17 sepsis cases and 23 severe sepsis cases) admitted to the intensive care unit (ICU), and 20 control cases. Results for urine sCD163 were recorded on the day of admission to the ICU, and AKI occurrence was noted. RESULTS: On the day of ICU admission, the sepsis group exhibited higher levels of urine sCD163 (74.8 ng/ml; range: 47.9-148.3 ng/ml) compared with those in the SIRS group (31.9 ng/ml; 16.8-48.0, P < 0.001). The area under the curve (AUC) was 0.83 (95% confidence interval [CI]: 0.72-0.94, P < 0.001) the sensitivity was 0.83, and the specificity was 0.75 (based on a cut-off point of 43.0 ng/ml). Moreover, the severe sepsis group appeared to have a higher level of sCD163 compared with that in the sepsis group (76.2; 47.2-167.5 ng/ml vs. 74.2; 46.2-131.6 ng/ml), but this was not significant. For 15 patients with AKI, urine sCD163 levels at AKI diagnosis were significantly higher than those of the remaining 35 sepsis patients upon ICU admission (121.0; 74.6-299.1 ng/ml vs. 61.8; 42.8-128.3 ng/ml, P = 0.049). The AUC for urine sCD163 was 0.688 (95% CI: 0.51-0.87, P = 0.049). Sepsis patients with a poor prognosis showed a higher urine sCD163 level at ICU admission (98.6; 50.3-275.6 ng/ml vs. 68.0; 44.8-114.5 ng/ml), but this was not significant. Patients with AKI with a poor prognosis had higher sCD163 levels than those in patients with a better prognosis (205.9; 38.6-766.0 ng/ml vs. 80.9; 74.9-141.0 ng/ml), but this was not significant. CONCLUSIONS: This study shows, for the first time, the potential value of urine sCD163 levels for identifying sepsis and diagnosing AKI, as well as for assessment of patients' prognosis. TRIAL REGISTRATION: ChiCTR-ONC-10000812.

Quantitative and qualitative urine protein excretion in dogs with severe inflammatory response syndrome.

BACKGROUND: Proteinuria is an established characteristic of renal disease in dogs, providing diagnostic and prognostic information. Little is known about the occurrence and severity of proteinuria in dogs with severe inflammatory response syndrome (SIRS). HYPOTHESIS: The quantitative and qualitative urinary protein (UP) excretion is altered in dogs with SIRS. ANIMALS: Thirty-nine dogs with SIRS and 15 healthy control dogs at admission. METHODS: A case control study was performed. Diagnosis of SIRS was based on clinical and clinicopathological findings. Urinary protein (UP) was measured by a colorimetric assay. Urinary albumin (UAlb) and urinary retinol-binding protein (URBP) were measured by ELISA and quantified in relation to urinary creatinine (UC). Sodium dodecyl sulfate polyacrylamid-gel electrophoresis was conducted to identify the qualitative pattern of proteinuria. Mann-Whitney U-test was used to assess differences in UP/UC, UAlb/UC and URBP/UC between the groups. P-values < .05 were considered significant. RESULTS: Dogs with SIRS had higher ratios of UP/UC, UAlb/UC and URBP/UC (all P < .001) in comparison to healthy control dogs. Dogs with SIRS had a total of 11 protein bands compared to 3 bands in healthy controls. In dogs with SIRS, 58% of the total counted bands were in the low molecular weight range (<60 kDa) whereas 42% were in the middle (60-80 kDa)/high molecular weight range (>80 kDa). CONCLUSIONS AND CLINICAL IMPORTANCE: SIRS alters UP excretion in dogs. Further studies should evaluate whether or not the magnitude of proteinuria is predictive of the severity and outcome of dogs with SIRS.

Neopterin as a prognostic biomarker in intensive care unit patients.

PURPOSE: The present study was undertaken to evaluate urinary neopterin in intensive care unit patients. MATERIALS AND METHODS: Urinary neopterin levels were determined in systemic inflammatory response syndrome (n = 10), sepsis (n = 18), septic shock (n = 9), and multiple organ dysfunction syndrome (n = 5). It was tested whether neopterin is a differential parameter among the patient groups. Furthermore, the results were also evaluated by comparing with a healthy control group (n = 30), and the relationship between neopterin and mortality or Acute Physiology and Chronic Health Evaluation II scores were investigated. RESULTS: Neopterin levels of the control group and patients were detected as 111 +/- 11 and 3850 +/- 1081 mumol/mol creatinine, respectively (P < .05). It was significantly increased in the sepsis and septic shock groups compared to the systemic inflammatory response syndrome group (P < .05). Neopterin levels were significantly higher in the patients with mortality and lower Acute Physiology and Chronic Health Evaluation II scores. CONCLUSION: This study showed that monitoring of urinary neopterin profile can be used in intensive care units to show the degree and prognosis of the disease.

Role of the kidney in plasma cytokine removal in sepsis syndrome: a pilot study.

BACKGROUND: At the onset of sepsis, endotoxins or other components of the gram-negative capsular wall stimulate the synthesis of pro-inflammatory cytokines by activating the monocyte-macrophage system. In this context, interleukin-1 beta (IL-1), tumor necrosis factor-alpha (TNF) and IL-6 are considered co-responsible for the clinical picture of sepsis syndrome. Many organs can be involved, and kidney dysfunction occurs early with a picture of non-oliguric acute renal failure (NOARF) or oliguric acute renal failure (OARF). This study aimed to investigate the role of the kidney in plasma removal of some pro-inflammatory cytokines in the first 24 hr after the diagnosis of sepsis syndrome, when, according to the peak concentration hypothesis, their plasma concentration is maximal. 18 septic patients, six patients with normal renal function (NRF), six with NOARF and six with OARF were selected for the study. We measured the plasma levels and urinary excretion of IL-1, TNF and IL-6 at the moment of sepsis diagnosis (base-line) and 24 hr later. Moreover, urinary excretion of IL-1 and IL-6 was done in the same interval by measuring the percentage of fractional excretion (FE%) of these cytokines. RESULTS: Multivariate analysis (ANOVA) showed no significant difference in plasma IL-1 levels at baseline in the NRF, NOARF and OARF patients (p=0.11), whereas a significant increase was found in OARF patients at 24 hr, p<0.023. OARF patients presented significantly higher IL-6 plasma levels compared with the other two groups, both at baseline (p<0.0002) and at 24 hr (p<0.0001). Plasma TNF levels were not significantly different at baseline (p=0.184), whereas the OARF group showed a significant increase at 24 hr, (p<0.05). The urinary FE of IL-1 was 1.2 +/- 0.6% in NRF, and 1.0 +/- 0.4% in NOARF (ns), the FE of IL-6 was 1.4 +/- 0.8% in NRF and 1.3 +/- 0.3% in NOARF (ns). A negative in-significant correlation was found between the plasma concentration and FE of IL-1 beta (r=-0.33, p<0.07). Urinary excretion of IL-6 was significantly related with urinary IL-1 beta, both expressed as pg/ml/mg of urinary creatinine (r=0.85, p<0.0001). No significant relation was found between IL-1 and IL-6 plasma concentrations or between plasma concentration and FE of IL-6. CONCLUSION: These results suggest that at disease onset, the kidney removes some pro-inflammatory cytokines from the plasma of septic patients until diuresis is preserved. As it has been demonstrated that NOARF patients have a better prognosis than OARF patients and their survival in sepsis syndrome seems to be inversely related to the plasma pro-inflammatory cytokine levels, diuresis maintenance by diuretic infusion can be important to improve patient prognosis.

Urinary excretion of deoxypyridinoline increases after gastrointestinal surgery.

OBJECTIVES: We investigated the effect of gastrointestinal surgery on bone metabolism with special reference to nutrition status and the systemic inflammatory response (SIR). METHODS: We assessed bone resorption by measuring the urinary excretion of deoxypyridinoline (D-Pyr), a specific marker that reflects the amount of degraded collagen. Twenty patients who underwent gastrectomy or colectomy were enrolled in this study. Daily energy intake, nitrogen, calcium, and phosphate balances, and urinary D-Pyr were examined preoperatively and for 14 days after the operation. The nutritional risk index and prealbumin were measured for nutrition assessment, and SIR was evaluated daily based on scorings of body temperature, pulse rate, respiratory rate, and white blood cell number according to our criteria. RESULTS: Urinary D-Pyr excretion had already increased on postoperative day 1 and continued to increase until postoperative day 14. The amounts of postoperative urinary excretion of D-Pyr correlated positively with the SIR scores and the amount of urinary excretion of cortisol, one of the stress-response hormones, and inversely with pre- and postoperative nutritional risk indices. In addition, the patients who experienced complications during the postoperative period excreted larger amounts of D-Pyr. CONCLUSIONS: Because the amount of excreted D-Pyr reflects the loss of the bone matrix, these results may indicate that bone resorption increases after gastrointestinal surgery. The extent of resorption was parallel to the degree of SIR and nutrition status.

Intestinal mucosal injury in critically ill surgical patients: preliminary observations.

This was a prospective study designed to evaluate the extent to which intestinal mucosal compromise occurs in adult critical care patients with and without systemic inflammatory response syndrome (SIRS) and to correlate the degree of intestinal injury with outcome. Ten patients from a university hospital surgical intensive care unit were identified who manifested SIRS at the time of admission to the intensive care unit. Five other critical care patients without SIRS were also evaluated. The Acute Physiology and Chronic Health Evaluation II score was determined. Intestinal mucosal viability was assessed by serial measurement of serum and urine iFABP intestinal fatty acid binding protein (iFABP), a sensitive and specific marker for mucosal injury. Outcome in terms of the development of multiorgan dysfunction syndrome, adult respiratory distress syndrome, and survival was determined. iFABP was detectable in the serum or urine in 8 out of 10 patients with SIRS. Among the 4 patients with detectable serum iFABP, 2 died and 1 developed severe adult respiratory distress syndrome. Nine of 11 patients without detectable serum iFABP recovered without major morbidity. iFABP was detectable in most patients with SIRS, suggesting that subclinical intestinal mucosal compromise is a frequent component of this syndrome. When iFABP was detectable, particularly in the serum, the prognosis was poor, even in the absence of SIRS, indicating that iFABP may be a relevant and independent predictor of outcome in critical care patients.

Organ failure, infection, and the systemic inflammatory response syndrome are associated with elevated levels of urinary intestinal fatty acid binding protein: study of 100 consecutive patients in a surgical intensive care unit.

BACKGROUND: Intestinal mucosal ischemia and subsequent barrier dysfunction have been related to the development of organ dysfunction and death in the critically ill. We hypothesized that urine concentrations of intestinal fatty acid binding protein (IFABP), a sensitive marker of intestinal ischemia, might predict the development of the systemic inflammatory response syndrome (SIRS) and organ dysfunction. METHODS: One hundred consecutive critically ill patients were prospectively studied for the development of infectious complications, organ dysfunction, and SIRS. Urine was collected daily for measurement of IFABP. RESULTS: A total of 58 males and 42 females (mean age, 56 years; range,16-85 years) were studied. Of these 100 patients, 40 patients developed complications and 5 patients developed SIRS. IFABP was significantly elevated in all patients with SIRS, and IFABP levels peaked an average of 1.4 days (range, 0-7 days) before the diagnosis of SIRS. CONCLUSION: Elevated concentrations of urine IFABP correlated with the clinical development of SIRS. Studies to assess the utility of IFABP as a predictor of organ dysfunction and SIRS in the critically ill are warranted.

Urinary nitrite excretion in low birth weight neonates with systemic inflammatory response syndrome.

Increased nitric oxide (NO) levels are thought to play an important role in the pathophysiology of the systemic inflammatory response syndrome (SIRS) which is caused by disseminated vascular endothelial damage. Clinical studies have shown that urinary nitrite (NO2-) and nitrate (NO3-) excretions can be utilized as indexes of NO formation. The SIRS and NO relationship was investigated in 15 neonates with SIRS, gestational age 32.5 +/- 4.4 weeks and weight 1,737 +/- 753 g. The control group comprised 18 neonates with a gestational age of 32.8 +/- 3.5 weeks and a weight of 1,778 +/- 538 g. There was no significant difference in birth weights and gestational ages between the two groups (p > 0.05 and p > 0.05). The urinary nitrite levels obtained in the subjects were normalized for urinary creatinine concentrations. The mean urinary nitrite levels in the control group neonates were found to be 4.22 +/- 1.8 micromol/mmol creatinine on the 1st day, 4.09 +/- 2.28 on the 2nd, 3.62 +/- 1.6 on the 3rd, and 4.01 +/- 1.12 micromol/mmol creatinine on the 7th day. There were no statistically significant differences between these levels (p > 0.05). We determined urinary levels of nitrite in neonates in the study group within the first 24 h of SIRS symptoms and found these levels (18.35 +/- 11.16 micromol nitrite/mmol creatinine) to be elevated as compared with those of the control subjects on the 7th day of life (p < 0.0005). In conclusion, urinary nitrite excretion is significantly elevated in neonates with SIRS due to septic events, and these results suggest that NO might play a part in SIRS.