Mystery called sarcoidosis: Forty-four years follow-up of chronic systemic disease

Introduction. This is a presentation of a 61-year-old female patient. Since 44 years have passed from the onset of her first symptoms until the final diagnosis of sarcoidosis, this was the reason of our decision to publish the case. Case Outline. During the follow-up period of 44 years the patient had ocassional polymorphic complains, such as adynamia, nausea, abdominal pains, myalgia, arthralgia, body weight loss (8-10 kg) etc. The clinical course was predominated by splenomegaly, hepatitis and arthralgia, and later chronic renal failure also developed. Laboratory findings showed elevated markers of acute inflammation and autoantibodies. The patient was hospitalized in different university internal hospitals (gastroenterology, allergology, rheumatology, nephrology and pulmology). Liver biopsy was performed three times, rectum and kidney biopsy once each and finally bronchoscopy and pulmonary biopsy was done. At last, about 40 years from the onset of the first symptoms, in 2006 the diagnosis of lung sarcoidosis was established. Conclusion. The final diagnosis of spleen sarcoidosis was confirmed by pathologically verified sarcoidosis of the lungs. This case is particularly interesting because of the presence of familial sarcoidosis (the patient’s son also had recurrent pulmonary sarcoidosis). [Projekat Ministarstva nauke Republike Srbije, br. 175046

Matrix Metalloproteinase-9 and Tissue Inhibitor of Matrix Metalloproteinase-1 in Sepsis after Major Abdominal Surgery

Background. The role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in sepsis after major abdominal surgery and sepsis-associated organ dysfunction is unexplored. Materials and Methods. Fifty-three patients with sepsis after major abdominal surgery were compared to 50 operated and 50 nonoperated controls. MMP-9, TIMP-1, biomarkers of inflammation, kidney and liver injury, coagulation, and metabolic disorders were measured daily during 96 h following diagnosis of sepsis and once in controls. MMP-9/TIMP-1 ratios and disease severity scores were calculated. Use of vasopressors/inotropes, mechanical ventilation, and survival were recorded. Results. Septic patients had lower MMP-9 and MMP-9/TIMP-1 ratios but higher TIMP-1 levels compared to controls. AUC-ROC for diagnosis of sepsis was 0.940 and 0.854 for TIMP-1 and 0.924 and 0.788 for MMP-9/TIMP-1 ratio (sepsis versus nonoperated and sepsis versus operated controls, resp.). Lower MMP-9 and MMP-9/TIMP-1 ratio and higher TIMP-1 levels were associated with shorter survival. MMP-9, TIMP-1, and MMP-9/TIMP-1 ratio correlated with biomarkers of inflammation, kidney and liver injury, coagulation, metabolic disorders, and disease severity scores. Use of vasopressors/inotropes was associated with higher TIMP-1 levels. Conclusions. MMP-9, TIMP-1, and MMP-9/TIMP ratio were good diagnostic or prognostic biomarkers of sepsis after major abdominal surgery and were linked to sepsis-associated organ dysfunction

Associations of Common Variants in HFE and TMPRSS6 Genes with Hepcidin-25 and Iron Status Parameters in Patients with End-Stage Renal Disease

Background. Influence of TMPRSS6 A736V and HFE (C282Y and H63D) polymorphisms on serum hepcidin-25 levels and iron status parameters in end-stage renal disease (ESRD) patients stratified according to gender has not been previously investigated. In addition, we aimed to evaluate the diagnostic accuracy of the parameters to separate iron-deficiency anemia (IDA) from anemia of chronic disease. Materials and Methods. Iron status parameters and genetic analysis were performed in 126 ESRD patients and in 31 IDA patients as the control group. Results. ESRD patients had significantly higher ferritin and hepcidin-25 ( lt 0.001) relative to IDA patients. Cut-off values with the best diagnostic accuracy were found for hepcidin 9.32ng/mL, ferritin 48.2g/L, transferrin saturation 16.8%, and MCV 81fL. Interaction between gender and HFE haplotypes for the hepcidin-25 and ferritin levels in ESRD patients (p=0.005, partial eta squared=0.09; p=0.027, partial eta squared=0.06, respectively) was found. Serum transferrin was influenced by the combined effect of gender and TMPRSS6 A736V polymorphism in ESRD patients (p=0.002, partial eta squared=0.07). Conclusion. Our findings could contribute to the further investigation of mechanisms involved in the pathophysiology and important gender-related involvement of the TMPRSS6 and HFE polymorphisms on anemia in ESRD patients

Tissue Kidney Injury Molecule-1 Expression in the Prediction of Renal Function for Several Years after Kidney Biopsy

Objectives. Retrospective study was designed to examine the importance of tissue kidney injury molecule-1 (KIM-1) expression in predicting kidney function in sixty patients (27 males) aged 34.15 +/- 12.23 years with different kidney diseases over three years after kidney biopsy. Materials and Methods. Tissue KIM-1 expression was determined immunohistochemically and KIM-1 staining was scored semiquantitatively, as well as tubulointerstitialis (TIN), inflammation, atrophy, and fibrosis. Kidney function (MDRD formula) and proteinuria/day were evaluated at the time of biopsy (GFR0) and 6, 12, 24, and 36 months later Results. Significantly positive correlations between tissue KIM-1 expression and age (r = 0.313), TIN inflammation (r = 0.456), fibrosis (r = 0.317), and proteinuria at 6 months (r = 0.394) as well as negative correlations with GFR0 (r = -0.572), GFR6 (r = -0.442), GFR24 (r = -0.398), and GFR36 (r = -0.412) were found. Meanwhile, TIN inflammation was the best predictor of all measured kidney functions during three years, while tissue KIM-1 expression (p = 0.016) was a predictor only at 6 months after biopsy. Conclusion. Tissue KIM-1 expression significantly predicts kidney function solely at 6 months after biopsy, when the effects of immune and nonimmune treatments are the strongest

The Pharmacokinetics of Recombinant Human Erythropoietin in Balkan Endemic Nephropathy Patients

Background: Balkan endemic nephropathy (BEN) hemodialysis patients require a higher dose of recombinant human erythropoietin for maintaining target hemoglobin level than patients with other kidney diseases. Objectives: Comparison of the pharmacokinetics of beta-erythropoietin given subcutaneously to hemodialysis patients with BEN or other kidney diseases (non-BEN). Methods: Recombinant human erythropoietin (75U/kg) was administered subcutaneously to 10 BEN and 14 non-BEN hemodialysis patients. The predose plasma level of erythropoietin (Epo) was subtracted from all postdose levels. The relevant pharmacokinetic parameters were calculated after noncompartmental pharmacokinetic analysis using Kinetica software (Thermo Scientific, ver.5.0). Results: Although basal plasma Epo concentration was similar in BEN (20.1 +/- 10.3U/L) and non-BEN (15.1 +/- 8.1U/L; p=.1964) patients, there were significant differences between the groups for elimination rate constant (0.016 +/- 0.006 vs 0.026 +/- 0.011 hr(-1); p=.020) and elimination half-life (50.24 +/- 19.12 vs 33.79 +/- 18.91 hr, p=.048). These differences remained significant after adjustment for patient characteristics (age, sex, hennodialysis duration, ferritin, PTH and ACEI use). No significant differences between groups were found in maximal Epo concentration, time to maximum Epo concentration, area under the curve from time of dosing extrapolated to infinity, clearance, mean residence time of Epo between groups both before and after adjustment. Conclusion: Pharmacokinetic analysis of beta-erythropoietin detected a significantly longer elimination half-life in BEN than in non BEN patients. This finding needs to be confirmed in a well-controlled study with a larger sample size

Serum lactate as reliable biomarker of acute kidney injury in low-risk cardiac surgery patients

Background: Cardiac surgery-associated acute kidney injury (CSA-AKI) frequently occurs in patients assessed as low-risk for developing CSA-AKI. Neutrophil Gelatinase-Associated Lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1) and lactate are promising biomarkers of CSA-AKI but have not yet been explored in low-risk patients. Aim: To evaluate urinary NGAL (uNGAL), KIM-1 and lactate as biomarkers of CSA-AKI in patients with low-risk for developing CSA-AKI. Methods: This prospective, observational study included 100 adult elective cardiac surgery patients assessed as low-risk for developing CSA-AKI. UNGAL, KIM-1 and lactate were measured preoperatively, at the end of cardiopulmonary bypass (CPB) and 3, 12, 24 and 48 h later. Results: Fifteen patients developed CSA-AKI. Patients with CSA-AKI had significantly higher lactate but similar uNGAL and KIM-1 levels compared to patients without CSA-AKI. Unlike uNGAL and KIM-1, postoperative lactate was good biomarker of CSA-AKI with the highest odds ratio (OR) 2.7 [1.4-4.9] 24 h after CPB. Peak lactate concentration >= 4 mmol/L carried dramatically higher risk for developing CSA-AKI (OR 6.3 [1.9-20.5]). Conclusions: Unlike uNGAL and KIM-1, postoperative lactate was significant independent predictor of CSA-AKI with the highest odds ratio 24 h after CPB

Downregulation of AdipoR1 is Associated with Increased Circulating Adiponectin Levels in Serbian Chronic Kidney Disease Patients

Background: Since the rise in plasma adiponectin levels in chronic kidney disease (CKD) patients has not yet been elucidated, we sought to investigate if patients on hemodialysis (HD) have altered expression of adiponectin receptors in peripheral blood mononuclear cells (PBMCs) compared to healthy subjects. Methods: This study included 31 patients with chronic kidney disease on HD and 33 healthy subjects (CG). Circulating adiponectin levels were measured by ELISA while AdipoR1 and AdipoR2 mRNA levels in PBMCs were determined by real-time PCR. Results: Plasma adiponectin levels were significantly higher in patients compared to control group (P=0.036). After adjustment for age, BMI and creatinine, this difference became even more significant (P=0.004). In both groups adiponectin correlated with creatinine (CG: r=-0.472, P=0.006; HD: r=-0.375, P=0.038), triglycerides (CG: r=0.490, P=0.004; HD: r=-0.488, P=0.005), insulin (CG: r=-0.386, P=0.038; HD: r=-0.506, P=0.012) and high density lipoprotein cholesterol (HDL-C) (CG: r=-0.672, P lt 0.001; HD: r=-0.584, P=0.001). Significantly lower expression of PBMCs AdipoR1 mRNA was found in patients compared to CG (P=0.034), while AdipoR2 mRNA levels were similarly expressed in PBMCs in both groups. Conclusions: Complex pathological processes in CKD cause downregulation of AdipoR1 which could ultimately influence AdipoR1 protein levels leading to a state of adiponectin resistance

Association of pentraxin-3, galectin-3 and matrix metalloproteinase-9/TIMP-1 with cardiovascular risk in renal disease patients

Inflammation, apoptosis and extracellular remodeling play significant roles in cardiovascular disease (CVD) underlying the major causes of mortality in renal patients. In 19 pre-dialysis patients, 21 dialysis patients and 20 control subjects, the concentrations of pentraxin-3, galectin-3, MMP-9 and TIMP-1 were determined by ELISA. CVD risk was calculated according to the Framingham risk score algorithm. Pentraxin-3 was increased in renal patients compared to healthy controls (p lt 0.001). In contrast, galectin-3 was reduced in hemodialysis patients compared to pre-dialysis patients and controls (p lt 0.001). In addition, MMP-9 and TIMP-1 were elevated in renal patients compared to controls (p lt 0.01 and p lt 0.001, respectively). Logistic regression analyses disclosed associations of galectin-3, MMP-9, pentraxin-3 and glomerular filtration with calculated CVD risk score. Combined testing of pentraxin-3, galectin-3, MMP-9 and glomerular filtration rate can discriminate renal patients with high and low risk of a coronary event

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 (O-2(center dot-)) 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 O-2(center dot-) to detect impaired FMD was investigated by receiving operative characteristic analysis. Hs-CRP (area under the curves (AUC) = 0.754, P lt 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 O-2(center dot-) 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

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