Relationship between European mitochondrial haplogroups and chronic renal allograft rejection in patients with kidney transplant.

Mitochondrial DNA variants may contribute to differences in mitochondrial function, leading to an altered immune system. The aim of this study was to analyze the relationship between mtDNA haplogroups and the development of chronic allograft dysfunction in patients with kidney transplant. A retrospective observational study was carried out on 261 patients who received kidney transplant (114 had stable transplant and 147 patients developed chronic allograft dysfunction). DNA samples were genotyped for 14 mtDNA polymorphisms by using Sequenom's MassARRAY platform (San Diego, CA, USA). Only European white patients within the N macro-cluster were included. Patients with haplogroups V (odds ratio (OR)=0.32; p=0.037) and J (OR=0.36; p=0.038) showed lower odds for developing CRAD than patients with haplogroup H. After adjusting for the most significant variables, haplogroups V and J tended to statistical significance (p=0.091 and p=0.067 respectively). This is a preliminary study in which mtDNA haplogroups seem to be implicated in susceptibility or protection for developing chronic allograft dysfunction.

Genetic polymorphisms located in genes related to immune and inflammatory processes are associated with end-stage renal disease: a preliminary study.

BACKGROUND: Chronic kidney disease progression has been linked to pro-inflammatory cytokines and markers of inflammation. These markers are also elevated in end-stage renal disease (ESRD), which constitutes a serious public health problem. OBJECTIVE: To investigate whether single nucleotide polymorphisms (SNPs) located in genes related to immune and inflammatory processes, could be associated with ESRD development. DESIGN AND METHODS: A retrospective case-control study was carried out on 276 patients with ESRD and 288 control subjects. Forty-eight SNPs were genotyped via SNPlex platform. Logistic regression was used to assess the relationship between each sigle polymorphism and the development of ESRD. RESULTS: Four polymorphisms showed association with ESRD: rs1801275 in the interleukin 4 receptor (IL4R) gene (OR: 0.66 (95%CI = 0.46-0.95); p = 0.025; overdominant model), rs4586 in chemokine (C-C motif) ligand 2 (CCL2) gene (OR: 0.70 (95%CI = 0.54-0.90); p = 0.005; additive model), rs301640 located in an intergenic binding site for signal transducer and activator of transcription 4 (STAT4) (OR: 1.82 (95%CI = 1.17-2.83); p = 0.006; additive model) and rs7830 in the nitric oxide synthase 3 (NOS3) gene (OR: 1.31 (95%CI = 1.01-1.71); p = 0.043; additive model). After adjusting for multiple testing, results lost significance. CONCLUSION: Our preliminary data suggest that four genetic polymorphisms located in genes related to inflammation and immune processes could help to predict the risk of developing ESRD.

Genetic polymorphisms located in TGFB1, AGTR1, and VEGFA genes are associated to chronic renal allograft dysfunction.

BACKGROUND: Persistent inflammation and fibrosis have been related to active progression of renal deterioration and reduced survival of kidney transplant. The aim of this study was to determine the impact of single-nucleotide polymorphisms (SNPs) located in regions related to inflammatory and immune processes on the development of chronic renal allograft dysfunction (CRAD). METHODS: A retrospective study was carried out on 276 patients who received kidney transplant (KT). SNPs were genotyped via the SNPlex platform. Statistical analysis was performed with SNPstat and regression logistic analyses were adjusted by age and gender of recipients and donors, cold ischemia time and the number of human leukocyte antigen (HLA) mismatches. RESULTS: From 276 patients with KT, 118 were non-CRAD and 158 were CRAD. Three SNPs showed significant associations with CRAD development: rs1800471 in transforming growth factor beta 1 (TGFB1), rs5186 in angiotensin II receptor type 1 (AGTR1), and rs699947 in vascular endothelial growth factor A (VEGFA). GC genotype of rs1800471 was associated with increased odds of CRAD compared to GG genotype (OR=2.65 (95% confidence interval (CI)=1.09; 6.47), p=0.025), as well as AC and AA genotype of rs699947 assuming a dominant model (OR=1.80 (95% CI=1.02; 3.20), p=0.044). Besides, AC and CC genotypes of rs5186 were associated with reduced odds of CRAD assuming a dominant model (OR=0.56 (95% CI=0.33; 0.96), p=0.033). CONCLUSION: Our findings suggest that three genes related to immunity and inflammation (rs1800471, rs5186 and rs699947) are associated to susceptibility or protection to CRAD, and might have diagnostic utility in predicting the likelihood of developing CRAD.

Postoperative kidney oxygen saturation as a novel marker for acute kidney injury after adult cardiac surgery.

OBJECTIVE: Acute kidney injury is a severe complication and one of the stronger risk factors for death in patients undergoing cardiac surgery. The relationship between postoperative brain oxygen saturation and kidney oxygen saturation with acute kidney injury in adults undergoing cardiac surgery has not been determined. We designed a single-center prospective study to determine if the continuous monitoring of postoperative brain oxygen saturation and kidney oxygen saturation could predict postoperative acute kidney injury. METHODS: We conducted a prospective open cohort study from January to September 2017. The primary outcome was postoperative acute kidney injury using the Kidney Disease: Improving Global Outcomes criteria. Brain oxygen saturation and kidney oxygen saturation, the metrics of which were area measurements (%-min), were recorded during the surgery and the first 48 hours after the cardiac procedure. Receiver operating characteristic curve analysis was used to evaluate the predictive power of kidney oxygen saturation for acute kidney injury. RESULTS: A total of 121 consecutive patients were enrolled. Thirty-five patients (28.9%) developed acute kidney injury. Brain oxygen saturation showed no statistical difference in both groups; however, kidney oxygen saturation was related to acute kidney injury (P = .001). Receiver operating characteristic curve analysis showed that kidney oxygen saturation could predict the risk of acute kidney injury. Kidney oxygen saturation less than 65% (area under the curve-receiver operating characteristic, 0.679 ± 0.054, 95% confidence interval, 0.573-0.785, P = .002) and 20% decrease from baseline (area under the curve-receiver operating characteristic, 0.639 ± 0.059, 95% confidence interval, 0.523-0.755, P = .019) showed the better performance, respectively. CONCLUSIONS: Postoperative kidney oxygen saturation is related to the development of cardiac surgery-associated acute kidney injury. Continuous kidney saturation monitoring might be a promising, noninvasive tool for predicting acute kidney injury during the postoperative period for adult patients after cardiac surgery.

Procalcitonin cannot be used as a biomarker of infection in heart surgery patients with acute kidney injury.

PURPOSE: We intended to assess how acute kidney injuy impacts on procalcitonin levels in cardiac surgery patients, with or without infection, and whether procalcitonin might be used as a biomarker of infection in acute kidney injuy. MATERIAL AND METHODS: A case-control study was designed which included patients that had had cardiac surgery between January 2011 and January 2015. Every patient developing severe sepsis or septic shock (n = 122; 5.5%) was enrolled. In addition, consecutive cardiac surgery patients during 2013 developing systemic inflammatory response syndrome (n = 318) were enrolled. Those recruited 440 patients were divided into 2 groups, according to renal function. RESULTS: Median procalcitonin levels were significantly higher during the 10 postoperative days in the acute kidney injury patients. Regression analysis showed that postoperatory day, creatinine, white blood cells and infection were significantly (P < .0001) associated to serum procalcitonin level. In patients with creatinine ≥2, median procalcitonin levels were similar in infected and non-infected patients. Only when creatinine was less than 2 mg/L, the median procalcitonin levels were significantly higher in patients with infection, as compared to those with no infection. CONCLUSIONS: In acute kidney injuy patients, high procalcitonin levels are a marker of acute kidney injuy but will not be able to differentiate infected from non-infected patients.

Predicting cardiac surgery-associated acute kidney injury: The CRATE score.

PURPOSE: Acute kidney injury (AKI) is a frequent complication after cardiac surgery and is associated with increased mortality. The aim was to design a nondialytic AKI score in patients with previously normal renal function undergoing cardiac surgery. METHODS: Data were collected on 909 patients who underwent cardiac surgery with cardiopulmonary bypass between 2012 and 2014. A total of 810 patients fulfilled the inclusion criteria. Patients were classified as having AKI based on the RIFLE criteria. Postoperative AKI occurred in 137 patients (16.9%). Several parameters were recorded preoperatively, intraoperatively, and at intensive care unit admission, looking for a univariate and multivariate association with AKI risk. A second data set of 741 patients, from 2 different hospitals, was recorded as a validation cohort. RESULTS: Four independent risk factors were included in the CRATE score: creatinine (odds ratio [OR], 9.66; 95% confidence interval [CI], 4.77-19.56; P < .001), EuroSCORE (OR, 1.40; CI, 1.29-1.52; P < .001), lactate (OR, 1.03; CI, 1.01-1.04; P < .001), and cardiopulmonary bypass time (OR, 1.01; CI, 1.01-1.02; P < .001). The accuracy of the model was good, with an area under the curve of 0.89 (CI, 0.85-0.92). The CRATE score retained good discrimination in validation cohort, with an area under the curve of 0.81 (95% CI, 0.78-0.85). CONCLUSIONS: CRATE score is an accurate and easy to calculate risk score that uses affordable and widely available variables in the routine care surgical patients.

Impact of ventilator-associated pneumonia on mortality and epidemiological features of patients with secondary peritonitis.

BACKGROUND: Despite the significant impact of nosocomial infections on the morbidity and mortality of patients staying in the intensive care unit (ICU), no study over the past 20 years has focused specifically on VAP following secondary peritonitis. The objective of the present study was to determine in-hospital mortality and epidemiological features attributed to ventilator-associated pneumonia (VAP) following secondary peritonitis. METHODS: Prospective observational study involved 418 consecutive patients admitted in the ICU. Univariate and multivariate analyses were performed to identify risk factors associated with mortality and development of VAP. RESULTS: The incidence of VAP following secondary peritonitis was 9.6 %. Risk factors associated with the development of VAP were hospital-acquired peritonitis, requiring >48 h of mechanical ventilation, and SOFA score. The onset of VAP was late in majority of patients. VAP was developed about 16.8 days after the initiation of the peritonitis. Etiological microorganisms responsible for the peritonitis were different than for VAP. The 90-day in-hospital mortality rate was 47.5 % of VAP patients. Independent factors associated with 30- to 90-day in-hospital mortality were VAP and SOFA. CONCLUSIONS: In light of the impact on morbidity and mortality in the ICU, more attention should be given to the concurrent features among VAP and secondary peritonitis.

Mitochondrial DNA haplogroups are associated with severe sepsis and mortality in patients who underwent major surgery.

OBJECTIVE: To analyse whether mitochondrial DNA (mtDNA) haplogroups are associated with severe sepsis and mortality after major surgery. METHODS: We performed a case-control study on 240 cardiac or abdominal surgery patients developing severe sepsis (Case-group) and 267 cardiac or abdominal surgery patients without severe sepsis and with systemic inflammatory response syndrome (SIRS, Control-group). Furthermore, a longitudinal substudy was performed for analysing the survival in septic patients. Only European white patients within the N macro-cluster were included. RESULTS: Case-group underwent cardiac surgery had lower frequencies of cluster HV (p = 0.005) and haplogroup H (p = 0.005) and higher frequencies of cluster JT (p = 0.028) than Control-group; but no significant differences were found for abdominal surgery. Besides, both cluster HV and haplogroup H were associated with decreased odds of severe sepsis (adjusted odds ratio (aOR) = 0.45 (95%CI = 0.25; 0.82); p = 0.009 and aOR = 0.48 (95%CI = 0.26; 0.87); p = 0.015, respectively) among patients underwent cardiac surgery. In Case-group, 45.4% (109/240) patients died with a survival median of 39 (95%CI = 31.4; 46.62) days. When the clusters were examined, 41% (55/134) patients within cluster HV died versus 71.4% (10/14) patients within cluster IWX (p = 0.018). Additionally, patients within cluster IWX had an increased risk of death (adjusted hazard ratio (aHR) = 2.22; (95%CI = 1.14; 4.34); p = 0.019). CONCLUSIONS: European mitochondrial haplogroups might be related to the onset of severe sepsis in patients who underwent major cardiac surgery, but not in patients underwent major abdominal surgery. Besides, mtDNA haplogroups could have influence on mortality in septic patients.

Ventilator-associated pneumonia is an important risk factor for mortality after major cardiac surgery.

PURPOSE: Ventilator-associated pneumonia (VAP) is the main infectious complication in cardiac surgery patients and is associated with an important increase in morbidity and mortality. The aim of our study was to analyze the impact of VAP on mortality excluding other comorbidities and to study its etiology and the risk factors for its development. MATERIALS AND METHODS: This prospective cohort study included 1610 postoperative cardiac surgery patients' status post cardiopulmonary bypass (CPB) between July 2004 and January 2008. The primary outcome measures were the development of VAP and in-hospital mortality. RESULTS: Ventilator-associated pneumonia was observed in 124 patients (7.7%). Patients with VAP had a longer length of hospitalization (40.7 ± 35.1 vs 16.1 ± 30.1 days, P < .0001) and greater in-hospital mortality (49.2% [61/124] vs 2.0% [30/1486], P = .0001) in comparison with patients without VAP. After performing the Cox multivariant analysis adjustment, VAP was identified as the most important independent mortality risk factor (adjusted hazard ratio [HR], 8.53; 95% confidence interval, 4.21-17.30; P = .0001). Other independent risk factors of in-hospital mortality were chronic renal failure (HR, 2.56), diabetes mellitus (HR, 1.90), CPB time (HR, 1.51), respiratory failure (HR, 2.13), acute renal failure (HR, 2.39), and mediastinal bleeding of at least 1000 mL (HR, 1.81). CONCLUSIONS: The development of VAP after CPB is the most important independent risk factor for in-hospital mortality. Identification of effective strategies for the prevention of VAP is needed.

Evolution of neutrophil apoptosis in septic shock survivors and nonsurvivors.

PURPOSE: The aims were to analyze the temporal evolution of neutrophil apoptosis, to determine the differences in neutrophil apoptosis among 28-day survivors and nonsurvivors, and to evaluate the use of neutrophil apoptosis as a predictor of mortality in patients with septic shock. MATERIALS AND METHODS: Prospective multicenter observational study carried out between July 2006 and June 2009. The staining solution study included 80 patients with septic shock and 25 healthy volunteers. Neutrophil apoptosis was assessed by fluorescein isothiocyanate (FITC)-conjugated annexin V and aminoactinomycin D staining. RESULTS: The percentage of neutrophil apoptosis was significantly decreased at 24 hours, 5 days, and 12 days after the diagnosis of septic shock (14.8% ± 13.4%, 13.4% ± 8.4%, and 15.4% ± 12.8%, respectively; P < .0001) compared with the control group (37.6% ± 12.8%). The difference in apoptosis between 28-day surviving and nonsurviving patients was nonsignificant (P > .05). The mortality rate at 28 days was 53.7%. The crude hazard ratio for mortality in patients with septic shock did not differ according to the percentage of apoptosis (hazard ratio, 1.006; 95% confidence interval, 0.98-1.03; P = .60). CONCLUSIONS: During the first 12 days of septic shock development, the level of neutrophil apoptosis decreases and does not recover normal values. No differences were observed between surviving and nonsurviving patients.

Beneficial role of endogenous immunoglobulin subclasses and isotypes in septic shock.

PURPOSE: There is increasing evidence on the relationship between endogenously produced immunoglobulins and the clinical outcome in septic shock (SS). MATERIALS AND METHODS: Levels of immunoglobulin G (IgG) subclasses, immunoglobulin A (IgA), immunoglobulin M (IgM), and immunoglobulin E were measured in plasma from 42 patients with SS and in 36 patients with systemic inflammatory response syndrome at diagnosis. Association of immunoglobulins levels with disease severity and outcome was evaluated. RESULTS: Eighteen patients with SS finally died. Both patients with systemic inflammatory response syndrome and SS showed subnormal levels of total IgG, IgG2, and IgM. Patients with SS who died showed the lowest levels of total IgG and IgG1. Total IgG, IgG1, IgG2, IgG3, IgG4, and IgA correlated inversely with Acute Physiology and Chronic Health Evaluation II score in SS. Univariate Cox regression analysis showed that levels of IgG1, IgG2, IgG3, IgM, IgA, and total IgG were inversely associated to the probability of death at 28 days. Multivariate analysis showed that IgG1, total IgG, IgM, and IgA behaved as independent protective factors against mortality (hazard ratio, P): 0.23, 0.026; 0.16, 0.028; 0.11, 0.042; 0.05, 0.010, respectively, whereas IgG3 showed a protective trend also. CONCLUSIONS: Our study evidenced that, in addition to IgG1, other major endogenous immunoglobulins isotypes and subclasses seem to play a beneficial role in SS.

Pro- and anti-inflammatory responses are regulated simultaneously from the first moments of septic shock.

The relationships between cytokine responses in septic shock are currently poorly understood. Some studies have pointed to a biphasic model, with an initial proinflammatory phase, followed by a reactive, anti-inflammatory response to explain the pathogenesis of the most severe form of sepsis. However, evidence for the coexistence of both responses has been found. In this study, the plasma levels of 17 cytokines and chemokines, in 20 patients with septic shock, 11 patients with systemic inflammatory response syndrome (SIRS), during the first 24 hours following diagnosis, and 10 healthy controls, were analyzed and compared. Patients with septic shock showed increased levels of IL-6, IL-8, MCP-1, MIP-1ß, IFN-γ, GM-CSF and IL-10 compared to healthy controls. Patients with SIRS showed higher levels of IL-6, IL-8, MCP-1, MIP-1ß, G-CSF and IL-10 than controls. Patients with septic shock showed higher levels of IL-8, GM-CSF, MIP-1ß than those with SIRS. The Spearman test demonstrated a positive association between the pro-inflammatory mediators IL-6, IL-8, MCP-1, MIP-1ß, IFN-γ, GM-CSF and the immunomodulatory cytokine IL-10 in septic shock. Consequently, correlation studies supported the notion that secretion of pro- and anti-inflammatory mediators in septic shock occurs as a simultaneous immune response program initiated early in the course of the disease, revealing that both types of cytokine play a role from the very beginning of this life-threatening condition.