Sanja Simic-Ogrizovic

A hazardous link between malnutrition, inflammation and oxidative stress in renal patients.

BACKGROUND Atherosclerosis is the main cause of mortality in end stage renal disease (ESRD) patients. DESIGN AND METHODS Malnutrition, inflammation and diminished paraoxonase activity were used to calculate the sum of risk factors for atherosclerosis development in a cohort of 141 chronic renal disease patients. Kaplan-Meier survival analysis was implemented to assess risk of death. RESULTS Kaplan-Meier analysis (Log rank=12.06, P=0.0072) showed higher risk of death with increasing number of risk factors in haemodialysis patients. CONCLUSIONS Malnutrition in combination with inflammation and oxidative stress is associated with higher mortality in patients on long-term haemodialysis.

Could the Level of Serum Albumin Be a Method for Assessing Malnutrition in Hemodialysis Patients

BACKGROUND Traditionally, serum albumin concentration has been used for assessing the nutrition status of hemodialysis patients despite evidence that the level is also affected by inflammation and many other underlying disorders frequently present in these individuals. The authors evaluated albumin as a nutrition parameter, comparing it with more specific anthropometric parameters. METHODS The study included a cohort of 271 patients. The analysis involved data obtained after patients entered the study (1994-2004). Anthropometric measurements included skinfolds, mid-arm circumference, mid-arm muscle circumference, percentage of body fat, body mass index, body height, and dry weight. Kt/V and normalized protein catabolic rate were also determined and laboratory analyses undertaken. RESULTS Serum albumin was only weakly correlated with mid-arm circumference (r = 0.12), mid-arm muscle circumference (r = 0.15), and fat-free mass (r = 0.12). Common factor analysis of nutrition parameters uncovered latent variables, but serum albumin was not associated strongly with them. The sensitivity of albumin in detecting malnutrition was 24%, with a specificity of 88% and a predictive value of 74%. Graphic analysis showed disagreement in albumin levels with percentage of body fat and mid-arm muscle circumference. CONCLUSION Serum albumin determination was shown to be a test with low sensitivity and specificity for evaluating malnutrition in hemodialysis patients. The values correlated weakly and showed graphic disagreement with anthropometric parameters. Therefore, methods that measure percentage of body fat and muscle mass should be used together or instead of serum albumin level for assessing the nutrition status of hemodialysis patients.

Cox proportional hazard model analysis of survival in end-stage renal disease patients with small-sized high-density lipoprotein particles

OBJECTIVE Dyslipidemia is commonly seen in patients with end-stage renal disease (ESRD). This prospective study investigates whether small-sized high-density lipoprotein (HDL) particles alone or in combination with high sensitivity C-reactive protein (hsCRP) are independent determinants of ESRD mortality. DESIGN AND METHODS We performed 36 months follow-up study in 122 haemodialysis (HD) patients. HDL size and subclass distribution were determined by gradient gel electrophoresis. Baseline characteristics of the patients were evaluated for the prediction of mortality. RESULTS Cox regressions analysis showed that patients with small-sized HDL particles had 2.8-fold higher risk of lethal outcome (P<0.05). Concomitant presence of small-sized HDL particles and increased hsCRP concentration were significantly associated with reduced survival rate (HR=3.907; P<0.05). Observed relationships persisted after adjustment for serum lipid and lipoprotein concentrations. CONCLUSIONS Our results indicate that small-sized HDL particles alone and combined with elevated hsCRP concentrations are independent predictors of reduced survival in HD patients.

Allopurinol and Enalapril Failed to Conserve Urinary NOx and Sodium in Ischemic Acute Renal Failure in Spontaneously Hypertensive Rats

Background: Ischemia-reperfusion-induced acute renal failure (ARF) is associated with a high mortality in patients with hypertension and with an unfavorable outcome of kidney transplants from marginal donors. Aim: The influence of allopurinol and enalapril on urinary nitrate/nitrite (UNOx), glomerular filtration rate, plasma and urinary sodium, and hemodynamic parameters was examined in spontaneously hypertensive rats (SHR) with ARF. Methods: ARF was induced by right-kidney removal and clamping the left renal artery for 40 min in 50 male 26-week-old SHR weighing 300 ± 23 g. The rats were randomly allocated to five groups: (1) sham operated; (2) ARF; (3) ARF after pretreatment with 40 mg/kg allopurinol; (4) ARF after pretreatment with 40 mg/kg enalapril, and (5) ARF after pretreatment with 40 mg/kg allopurinol and 40 mg/kg enalapril. Creatinine clearance, UNOx (Griess reaction), cardiac output (dye dilution technique), mean arterial blood pressure, and renal blood flow were measured 24 h after reperfusion. Total vascular resistance and renal vascular resistance were calculated and compared between the groups. Results: A nonsignificant decrease was found in both daily UNOx excretion and creatinine clearance when pretreated ARF groups and the ARF group without pretreatment were compared (p > 0.05). Significantly lower plasma sodium values (139.5 ± 4.86 mmol/l) in the allopurinol-pretreated ARF group were found than in the ARF group without pretreatment, in the ARF group pretreated with enalapril, and in the sham SHR group (p = 0.029). The urinary sodium loss was greater in the enalapril-pretreated than in the allopurinol-pretreated ARF group (p = 0.047). Allopurinol and/or enalapril pretreatment decreased total vascular resistance (p = 0.003) in comparison with the sham SHR group. Conclusion: Neither allopurinol nor enalapril nor both were protective against ischemia-reperfusion injury in SHR, nor altered glomerular filtration rate and UNOx in a favorable direction.

Low paraoxonase 1 activity predicts mortality in surgical patients with sepsis.

Introduction. State of severe oxidative stress is encountered in sepsis. Paraoxonase 1 (PON1) protects against oxidative stress but also undergoes inactivation upon that condition. We investigated PON1 activity in surgical patients with sepsis in relation to oxidative stress status, inflammation, disease severity, and survival. Methods. Prospective observational study. Sixty-nine surgical patients with sepsis were compared to 69 age/sex matched healthy controls. PON1 paraoxonase and diazoxonase activities, selected biochemical, hematological and oxidative stress parameters were measured on admission to ICU and 24, 48, 72, and 96 hours later. Disease severity scores were calculated daily. Results. Septic patients had significantly lower PON1 activities compared to control group at all time points. PON1 activities had good capacity to differentiate septic patients from healthy controls. Low PON1 activities were associated with higher disease severity scores and higher risk of death. Correlation between PON1 activity and markers of inflammation failed to reach significance. Decrease in PON1 activity was correlated with an increase in reducing components in plasma. Conclusion. Our study demonstrated lower PON1 activity in surgical patients with sepsis compared to healthy controls. PON1 activity also reflected severity of the disease. Low PON1 activity was associated with higher mortality of surgical patients with sepsis.

Nerve Conduction Studies and Prediction of Mortality in Hemodialysis Patients

Background. The electrophysiological aspects of uremic neuropathy have been studied extensively, but never for prediction of mortality. In order to assess the parameters of nerve conduction study (NCS) as predictors of mortality in hemodialysis patients, a post hoc analysis of a prospective observation study was made. Methods. We examined conventional electrophysiological parameters (motor nerve conduction velocity [MCV], terminal latency [TL], and F wave latency of the peroneal nerve, as well as sensory nerve conduction velocity [SCV] of the sural nerve) in 75 nondiabetic patients. Hemodialysis modality (bicarbonate dialysis and biocompatible membranes), Kt/V, comorbidity (ischemic heart disease and congestive heart failure), and clinical and laboratory parameters were also evaluated. Survival was analyzed using the Cox proportional hazard model. Results. SCV was significantly higher (t-test, p < 0.01) in the group of patients treated with polysulfone compared to those using cuprophane membranes. On the other hand, MCV significantly correlated with Kt/V (Pearson, r = 0.388; p < 0.01). Multivariate Cox regression revealed only MCV as a significant predictor of mortality in this group of hemodialysis patients (HR = 0.92; CI (0.86–0.99); p < 0.05). Conclusion. Only MCV was a significant mortality risk predictor among NCS parameters. This parameter correlates significantly with dialysis dose. SCV was related to the use of biocompatible membranes, indicating the complexity of polyneuropathy in dialysis patients.

Diagnostic Value of Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis-Associated Acute Kidney Injury

Sepsis-associated acute kidney injury (SA-AKI) severely impacts morbidity and mortality in surgical patients with sepsis. Matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) have an important role in pathophysiology of sepsis but they have been unexplored in SA-AKI. We aimed to investigate the role of MMP-9 and TIMP-1 in septic surgical patients with SA-AKI and to evaluate them as diagnostic biomarkers of SA-AKI. This prospective observational study compared 53 major abdominal surgery patients with sepsis divided into SA-AKI (n = 37) and non-SA-AKI (n =16) group to 50 controls without sepsis matched by age, gender, comorbidities and type of surgery. Blood and urine samples from septic patients were collected on admission to ICU and 24, 48, 72 and 96 h later and once from the controls. The levels of MMP-9, TIMP-1, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1, urea and creatinine were measured. MMP-9/TIMP-1 ratio and disease severity scores, such as Sequential Organ Failure Assessment (SOFA), were calculated. Septic patients with SA-AKI had higher serum TIMP-1 levels and lower serum MMP-9 levels and lower MMP-9/TIMP ratio, compared to septic patients without SA-AKI and controls. The levels of these biomarkers did not change significantly over time. MMP-9, TIMP-1 and MMP-9/TIMP-1 ratio correlated with urea, creatinine, NGAL, and SOFA scores. Moreover, using the area under ROC curve, we showed that TIMP-1 and MMP-9/TIMP-1 ratio, but not MMP-9, were good diagnostic biomarkers of SA-AKI. We report for the first time the potential diagnostic value of TIMP-1 and MMP-9/TIMP-1 ratio in SA-AKI.

Assessment of endothelial dysfunction: the role of symmetrical dimethylarginine and proinflammatory markers in chronic kidney disease and renal transplant recipients.

Objectives. The study was designed to evaluate associations between symmetric dimethylarginine (SDMA), inflammation, and superoxide anion (O2∙−) with endothelial function and to determine their potential for screening of endothelial dysfunction in patients with chronic kidney disease (CKD) and renal transplant (RT) recipients. Materials and Methods. We included 64 CKD and 52 RT patients. Patients were stratified according to brachial artery flow-mediated dilation (FMD). Results. Logistic regression analysis showed that high SDMA and high sensitive C-reactive protein (hs-CRP) were associated with impaired FMD in CKD and RT patients, after adjustment for glomerular filtration rate. The ability of inflammation, SDMA, and O2∙− to detect impaired FMD was investigated by receiving operative characteristic analysis. Hs-CRP (area under the curves (AUC) = 0.754, P < 0.001), IL-6 (AUC = 0.699, P = 0.002), and SDMA (AUC = 0.689, P = 0.007) had the highest ability to detect impaired FMD. SDMA in combination with inflammatory parameters and/or O2∙− had better screening performance than SDMA alone. Conclusions. Our results indicate a strong predictable association between hs-CRP, SDMA, and endothelial dysfunction in CKD patients and RT recipients. The individual marker that showed the strongest discriminative ability for endothelial dysfunction is hs-CRP, but its usefulness as a discriminatory marker for efficient diagnosis of endothelial dysfunction should be examined in prospective studies.

Inflammatory markers as mortality predictors in continuous ambulatory peritoneal dialysis patients

Abstract Background/Aim: Besides peritonitis, the most common complication, indicators of chronic inflammation are also present in patients treated by peritoneal dialysis. The aim of this study was to analyze the predictive value of inflammatory parameters on mortality of continuous ambulatory peritoneal dialysis (CAPD) patients. Methods: Eighty-seven patients (57 males), aged from 30 to 85 [62.92 (10.61)] years who had been treated by a chronic program of CAPD for 3–113 months were analyzed. The basal period lasted 3 months with a follow-up of 30 months. Clinical parameters, dialysis adequacy and laboratory parameters including some inflammatory markers: serum amyloid-A (SAA), high sensitive C-reactive protein (hs-CRP), fibrinogen, erythrocyte sedimentation rate (ESR) and leukocytes were determined for each patient. Cox regression analysis selected the parameters of univariate and multivariate survival analysis. Results: During the follow-up period, 37 patients (42.5%) died. Univariate analysis selected the following potential mortality predictors (p < 0.10): age, months on CAPD, residual urine output, presence of cerebrovascular insult (CVI), KT/V, serum urea and albumin concentrations, SAA, hs-CRP, fibrinogen and ESR. In the multivariate survival analysis four models were created, each with a single inflammatory parameter. In all of these models, besides the age and CVI, inflammatory parameters were the most significant mortality predictors. When the inflammatory markers were analyzed altogether, multivariate analysis established that independent mortality predictors in this group of patients were: SAA, age and CVI. Conclusion: It may be concluded that in this studied group treated by CAPD, SAA was the most significant independent mortality predictor among the analyzed inflammatory markers.

Association of small, dense low-density lipoprotein cholesterol and galectin-3 in patients with chronic kidney disease

Abstract Background. Dyslipidemia is a common feature of chronic kidney disease (CKD). Although it has been observed that the pattern of lipid abnormalities can vary according to the stage of CKD, there is lack of data concerning the distribution of lipoprotein subclasses at various stages of the disease. In addition, association of proatherogenic small, dense low-density lipoprotein (sdLDL) subclasses with markers of inflammation, such is galectin-3, is not sufficiently explored. The aim of this study was to analyze concentrations and relative proportions of sdLDL-cholesterol (sdLDL-C) and galectin-3 in patients with CKD, with respect to the stage of the disease. Also, we sought possible independent associations of galectin-3 and sdLDL-C. Methods. The study involved 100 hemodialysis (HD) and 50 pre-dialysis patients, together with 94 healthy individuals. SdLDL-C was measured by heparin–magnesium precipitation method. Galectin-3 was measured by ELISA technique. Results. Galectin-3 levels were higher in pre-dialysis and HD patients than in the control group (p < 0.01). The concentration of sdLDL-C was highest in the pre-dialysis group and lowest in HD patients (p < 0.01). CKD patients with increased galectin-3 concentrations had significantly higher relative proportions of cholesterol in sdLDL (% sdLDL-C) than their counterparts with lower galectin-3 levels (p < 0.05). Relative proportion of sdLDL-C was shown to be an independent determinant of galectin-3 concentration. Conclusions. Our results demonstrated alterations in concentrations and proportions of sdLDL-C according to the stages of CKD. The observed independent associations of % sdLDL-C and galectin-3 provide further insight into their complex interaction during the progression of atherosclerosis in CKD.