Serpil Muge Deger

The Relationship between the MEFV Genotype, Clinical Features, and Cytokine-Inflammatory Activities in Patients with Familial Mediterranean Fever

Familial Mediterranean Fever (FMF) is an autosomal recessive disease characterized by periodic attacks of fever and polyserositis. The effects of the MEFV genotype differences on clinical picture and inflammatory activity have not been well documented. The aim of this study was to investigate levels of conventional inflammation markers, procalcitonin, interleukin levels, TNF-alpha, and C5a levels in patients with FMF who had different MEFV genotypes and compare them with those of healthy subjects. The study consisted of 41 patients with FMF (F/M: 23/18), and 31 healthy subjects (F/M: 18/13). Tests were performed during the attack-free period. White-blood cell count, CRP and IL-8 levels were higher in patients with FMF than in healthy subjects (p < 0.05) and also higher in M680I carriers than in the patients with M694V allele carriers. However, ESR, fibrinogen, procalcitonin, IL-6, C5a, TNF-alpha, and IgD levels were not significantly different between patients and healthy subjects (p > 0.05). Arthralgia or arthritis was significantly higher in M694V carriers than in non-M694V carriers (p < 0.05). It is concluded that the clinical features and inflammatory-cytokine activities were higher in patients with FMF during the attack-free period than in healthy subjects, and the different genotype might be related to different clinical pictures.

Recent advances in acute kidney injury epidemiology.

Purpose of reviewExpanding rates of acute kidney injury (AKI) coupled with increasing awareness of its short-term and long-term sequelae have focused efforts to identify patients at risk for this disease and its complications. This review details the recent attempts to identify novel risk factors for AKI, describes further refinements in the diagnostic and prognostic approach using biological markers of injury, and highlights the features of AKI that independently predict poor long-term outcomes. Recent findingsThe presence of proteinuria predicts the development of AKI independently of estimated glomerular filtration rate. Initial results from a large prospective study of AKI biomarkers in cardiac surgery indicate lower agreement with serum creatinine as an AKI standard than observed in early studies. AKI severity and duration are important predictors of chronic kidney disease and long-term mortality. A minority of patients surviving AKI with decreased kidney function is seen by a nephrologist. SummaryAlthough the pathophysiologic link is unclear, proteinuria is an easily measurable risk factor for AKI worth considering before anticipated procedures or medication exposures carrying nephrologic risk. Investigation extending beyond agreement with serum creatinine is needed to fully understand the diagnostic and prognostic value of AKI biomarkers. Severity and duration are components of AKI that can help risk-stratify survivors in need of monitoring or nephrology referral.

Uric Acid is an Important Predictor for Hypertensive Early Atherosclerosis

IntroductionThe association between hyperuricemia and cardiovascular disease in hypertensive subjects is controversial. Attempts to elucidate the possible association between hyperuricemia and early atherosclerosis in hypertensive patients may provide alternative prevention or therapy targets for future cardiovascular events.MethodsA total of 67 hypertensive and 30 healthy subjects underwent B-mode ultrasonography to measure carotid intima media thickness (C-IMT). All biochemical analyses were assessed by local laboratories using standard laboratory methods.ResultsC-IMT, serum uric acid (UA) levels, and mean arterial blood pressure (MBP) levels were significantly higher in hypertensive population compared to healthy subjects (P<0.001). Among hypertensive subjects, high sensitivity C-reactive protein (hs-CRP), C-IMT, and proteinuria levels were significantly higher in hyperuricemic patients compared to normouricemic participants (for all, P<0.05). Age (r=0.28, P=0.02), MBP (r=0.34, P=0.04), hs-CRP (r=0.58, P=0.006), proteinuria (r=0.58, P=0.007), estimated glomerular filtration rate (r=−0.35, P=0.02), and UA (r=0.31, P=0.02) levels were significantly associated with C-IMT levels. Multiple linear regression analysis using C-IMT as a dependent variable showed that age (beta=0.84, P=0.03) and UA levels (beta=−0.87, P=0.02) were independently associated with C-IMT.ConclusionHyperuricemia is an independent predictor for early atherosclerosis in hypertensive subjects with normal renal function. Therefore, the optimal control of UA may provide further benefits in preventing atherosclerosis and hypertensive end-organ injury.

Predictive markers of asymptomatic atherosclerosis in end-stage renal disease patients

Objective: Uremia is associated with accelerated atherosclerosis and increased cardiovascular mortality in patients with end-stage renal disease (ESRD). Cardiac injury markers, such as myoglobin, creatine kinase-MB (CK-MB), or troponins, frequently used to recognize acute coronary events, may be falsely elevated in this patient group. In this study, our aim was to (i) test serum levels of myoglobin, CK-MB, and troponin I (cTnI) in ESRD patients without coronary artery disease (CAD) and compare the results with healthy controls and (ii) to investigate the association between these markers and carotid artery intima–media thickness (CA–IMT), high-sensitive C-reactive protein (hs-CRP), and serum uric acid (SUA) levels in ESRD patients. Materials and methods: Fifty-two ESRD patients (25 hemodialysis and 27 peritoneal dialysis) and 17 healthy controls were included in the study. Serum levels of myoglobin, CK-MB, and cTnI were measured and ultrasonographic CA–IMT was determined in all participants. SUA and hs-CRP levels were only measured in the ESRD group. Results: Serum myoglobin, CK-MB levels, and the mean CA–IMT were significantly higher in ESRD group (p < 0.01), whereas cTnI levels were not different compared to healthy controls (p = 0.70). There was also a positive correlation between CA–IMT and cTnI levels (p = 0.003, r = 0.35) and CA–IMT and hs-CRP (p = 0.03, r = 0.30) or SUA levels (p = 0.003, r = 0.43). Conclusion: cTnI may serve as a more sensitive marker in detecting cardiovascular events in patients with renal failure. Besides the traditional risk factors of atherosclerosis, cTnI, hs-CRP, and SUA may have a predictive role in recognizing premature atherosclerosis in ESRD patients.

Insulin Resistance and Protein Metabolism in Chronic Hemodialysis Patients

OBJECTIVE Loss of lean body mass (sarcopenia) is associated with increased morbidity and mortality in patients receiving chronic hemodialysis (CHD). Insulin resistance (IR), which is highly prevalent in patients receiving CHD, has been proposed to play a critical role in the development of sarcopenia. The aim of this study was to examine the effect of IR on amino acid metabolism in patients receiving CHD. DESIGN This was a cross-sectional study. SUBJECTS The study included 12 prevalent (i.e., patients that have been on dialysis for more than 90 days) African American patients receiving CHD. METHODS IR was measured as glucose disposal rate (GDR) determined from hyperinsulinemic euglycemic clamp (HGEC) studies performed 3 consecutive times. Plasma amino acid (AA) concentrations were measured by real-time high-performance liquid chromatography (HPLC) throughout the clamp study. The primary outcome was percentage change in leucine concentrations during the clamp study. The main predictor was the GDR measured simultaneously during the HGEC studies. Mixed model analysis was used to account for repeated measures. RESULTS All individual AA concentrations declined significantly in response to high-dose insulin administration (P < .001). There was a significant direct association between GDR by HECG studies and the percentage change in leucine concentration (P = .02). Although positive correlations were observed between GDR values and concentration changes from baseline for other AAs, these associations did not reach statistical significance. CONCLUSIONS Our results suggest that the severity of IR of carbohydrate metabolism is associated with a lesser decline in plasma leucine concentrations, suggesting a similar resistance to protein anabolism. Insulin resistance represents a potential mechanism for sarcopenia commonly observed in patients receiving CHD.

Wegener's granulomatosis with massive gastrointestinal hemorrhage due to jejunal and colonic involvement: report of a case.

Wegener’s granulomatosis (WG) is a systemic necrotizing vasculitis of unknown etiology characterized mainly by the involvement of the upper airways, lungs, and kidneys. Although most organ systems can be involved, gastrointestinal involvement in WG is notably uncommon. We herein present the case of a WG patient who developed two massive gastrointestinal hemorrhages treated respectively by surgery and angiographic embolization of the bleeding artery. The present case indicates that gastrointestinal manifestations might thus be considered in the natural history of WG.

Systemic inflammation is associated with exaggerated skeletal muscle protein catabolism in maintenance hemodialysis patients

BACKGROUND Systemic inflammation and muscle wasting are highly prevalent and coexist in patients on maintenance hemodialysis (MHD). We aimed to determine the effects of systemic inflammation on skeletal muscle protein metabolism in MHD patients. METHODS Whole body and skeletal muscle protein turnover were assessed by stable isotope kinetic studies. We incorporated expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue from integrin β1 gene KO CKD mice models. RESULTS Among 129 patients with mean (± SD) age 47 ± 12 years, 74% were African American, 73% were male, and 22% had diabetes mellitus. Median high-sensitivity C-reactive protein (hs-CRP) concentration was 13 (interquartile range 0.8, 33) mg/l. There were statistically significant associations between hs-CRP and forearm skeletal muscle protein synthesis, degradation, and net forearm skeletal muscle protein balance (P < 0.001 for all). The associations remained statistically significant after adjustment for clinical and demographic confounders, as well as in sensitivity analysis, excluding patients with diabetes mellitus. In attempting to identify potential mechanisms involved in this correlation, we show increased expressions of E1, E214K, E3αI, E3αII, MuRF-1, and atrogin-1 in skeletal muscle tissue obtained from an animal model of chronic kidney disease. CONCLUSION These data suggest that systemic inflammation is a strong and independent determinant of skeletal muscle protein homeostasis in MHD patients, providing rationale for further studies using anticytokine therapies in patients with underlying systemic inflammation. FUNDING This study was in part supported by NIH grants R01 DK45604 and 1K24 DK62849, the Clinical Translational Science Award UL1-TR000445 from the National Center for Advancing Translational Sciences, the Veterans Administration Merit Award I01 CX000414, the SatelliteHealth Normon Coplon Extramural Grant Program, and the FDA grant 000943.

Tissue sodium accumulation and peripheral insulin sensitivity in maintenance hemodialysis patients

Recent data suggest that sodium (Na+) is stored in the muscle and skin without commensurate water retention in maintenance hemodialysis (MHD) patients. In this study, we hypothesized that excessive Na+ accumulation would be associated with abnormalities in peripheral insulin action.

DNA damage in hemodialysis patients with chronic kidney disease; a test of the role of diabetes mellitus; a comet assay investigation

The incidence of chronic kidney disease (CKD) is increasing rapidly. Diabetes mellitus (DM) is the most important cause of CKD. We studied the possible role of DM in CKD patients with respect to DNA damage, as assessed by the comet assay in 60 CKD patients (with or without DM) undergoing hemodialysis and in 26 controls. Effects of other factors, such as age, sex, hypertension, duration of hemodialysis, body mass index (BMI), and levels of hemoglobin (HB), intact parathormone (iPTH), and ferritin (FER), were also examined. Primary DNA damage measured by the comet assay was significantly higher in CKD patients than in controls. Among CKD patients, the following correlations were observed. (1) There was no difference in comet tail length or tail intensity between diabetic and non-diabetic individuals. (2) Age, sex, hemoglobin, hypertension, duration of hemodialysis, and ferritin levels affected neither tail length nor intensity. (3) BMI values above 25kg/m(2) and iPTH levels above 300pg/ml were associated with significantly greater comet tail length. Our results indicate that primary DNA damage is increased in CKD patients undergoing hemodialysis, compared to controls; however, DM had no additional effect.

High Dose Omega-3 Fatty Acid Administration and Skeletal Muscle Protein Turnover in Maintenance Hemodialysis Patients

BACKGROUND AND OBJECTIVES Protein energy wasting and systemic inflammation are prevalent in maintenance hemodialysis (MHD) patients. Omega-3 (ω-3) fatty acids have anti-inflammatory properties and have been shown to improve protein homeostasis. We hypothesized that administration of high-dose (2.9 g/d) ω-3 would be associated with decreased muscle protein breakdown in MHD patients with systemic inflammation. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS This is a substudy from a randomized, placebo-controlled study (NCT00655525). Patients were recruited between September 2008 and June 2011. Primary inclusion criteria included signs of chronic inflammation (average C-reactive protein of ≥5 mg/L over three consecutive measurements), lack of active infectious or inflammatory disease, no hospitalization within 1 month prior to the study, and not receiving steroids (>5 mg/d) and/or immunosuppressive agents. The primary outcomes were forearm muscle and whole body protein breakdown and synthesis before and after the intervention. The patients received ω-3 (n=11) versus placebo (n=9) for 12 weeks. Analysis of covariance was used to compare outcome variables at 12 weeks. Models were adjusted for a propensity score that was derived from age, sex, race, baseline high sensitivity C-reactive protein, diabetes mellitus, and fat mass because the groups were not balanced for several characteristics. RESULTS Compared with placebo, ω-3 supplementation was significantly associated with decreased muscle protein breakdown at 12 weeks (-31, [interquartile range, -98--13] versus 26 [interquartile range, 13-87] µg/100 ml per min; P=0.01), which remained significant after multivariate adjustment (-46, [95% confidence interval, -102 to -1] µg/100 ml per min). ω-3 Supplementation resulted in decreased forearm muscle protein synthesis while the rate in the placebo group increased; however, there is no longer a statistically significant difference in skeletal muscle protein synthesis or in net protein balance after multivariate adjustment. There was no statistically significant effect of ω-3 supplementation on whole body protein synthesis or breakdown. CONCLUSIONS High-dose ω-3 supplementation over 12 weeks in MHD patients with systemic inflammation was associated with attenuation of forearm muscle protein breakdown but did not influence skeletal muscle protein synthesis, skeletal muscle net protein balance or any component of the whole-body protein balance. These results should be interpreted cautiously given the imbalance in the two groups and the short duration of the intervention.