Increase In Cystatin Research Articles

Cystatin C and Cardiac Measures in Children and Adolescents With CKD

Cardiovascular disease (CVD) is highly prevalent among children with chronic kidney disease (CKD). Cystatin C is an established marker of kidney function and an emerging biomarker for CVD events. We quantified the relationship between cystatin C level and cardiac structure and function over time among children with CKD and assessed whether cystatin C level and diastolic function retained an association after accounting for kidney function. Prospective cohort study. 678 children and adolescents with mild to moderate CKD enrolled in the CKD in Children (CKiD) Study with 1,228 echocardiographically obtained cardiac structure and function measurements. Serum cystatin C (mg/L) measured annually. Cardiac structure (left ventricular mass index [g/m2.7]) and cardiac function (shortening fraction; E/A, E'/A', E/E' ratios) measured every other year. Demographics and anthropometrics, measured glomerular filtration rate (mGFR), heart rate, blood pressure, hemoglobin z score, serum albumin level, and calcium-phosphorus product. Independent of time, each 1-mg/L increase in cystatin C level was independently associated with a concurrent 7.7% (95% CI, 5.3%-10.0%) increase in left ventricular mass index, a-4.7% (95% CI,-7.0% to-2.4%) change in E/A ratio, a-6.6% (95% CI,-9.0% to-4.2%) change in E'/A' ratio, and a 2.5% (95% CI, 0.3%-4.7%) increase in E/E' ratio. mGFR was also independently associated with E'/A' ratio. When cystatin C level and mGFR were included in the same model, cystatin C level remained independently associated with E'/A' ratio, whereas mGFR was not. 24% of the cohort was missing data for outcomes of interest or measurements; study population includes only children and adolescents with mild to moderate CKD. In this study of children and adolescents with mild to moderate CKD, cystatin C level was independently associated with cardiac structure and diastolic function. Cystatin C level remained able to predict diastolic function decline via E'/A' ratio even after adjusting for mGFR, suggesting that cystatin C level may have an independent role in CVD risk stratification among children and adolescents with CKD.

Anti-Inflammatory Effects and Prediction of Blood Pressure Response by Baseline Inflammatory State in Catheter-Based Renal Denervation.

This retrospective analysis aimed to examine off-target effects on inflammatory and renal function parameters in n=78 subsequent patients treated with renal denervation (RDN) for resistant hypertension. Ambulatory and office blood pressure (ABP/OBP), serum creatinine, glomerular filtration rate (GFR), cystatin C, C-reactive protein (CRP), interleukin-6 (IL-6), and white blood cell count (WBC) were assessed before, 6 and 12 months after RDN. ABP was significantly reduced by -8.2/-3.8 mm Hg (P=.002/.021) at 1 year after RDN, while an initial OBP reduction was not sustained during follow-up. IL-6 levels significantly decreased by -0.5 pg/mL (P=.042) and by -1.7 pg/mL (P<.001) at 6 and 12 months, baseline IL-6 levels possibly predicting ABP response to RDN (r=-0.295; P=.020). Concurrently, leukocyte count was reduced by -0.5 × 103 /μL (P=.017) and -0.8 × 103 /μL (P<.001), respectively. Serum creatinine and GFR remained unchanged, but we observed a significant increase in cystatin C by 0.04 mg/L (P=.026) and 0.14 mg/L (P<.001) at 6 and 12 months after the intervention.

Association of Peak Changes in Plasma Cystatin C and Creatinine With Death After Cardiac Operations

Acute kidney injury is a risk factor for death in cardiac surgical patients. Plasma cystatin C and creatinine have different temporal profiles in the postoperative setting, but the associations of simultaneous changes in both filtration markers compared with change in only one marker with prognosis after hospital discharge are not well described. This is a longitudinal study of 1,199 high-risk adult cardiac surgical patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium who survived hospitalization. We examined in-hospital peak changes of cystatin C and creatinine in the 3 days after cardiac operations. We evaluated associations of these filtration markers with death, adjusting for demographics, operative characteristics, medical comorbidities, preoperative estimated glomerular filtration rate, preoperative urinary albumin-to-creatinine ratio, and site. During the first 3 days of hospitalization, nearly twice as many patients had a 25% or higher rise in creatinine (30%) compared with a 25% or higher peak rise in cystatin C (15%). The risk of death was higher in those with elevations in cystatin C (adjusted hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.4 to 2.37) or creatinine (adjusted HR, 1.90; 95% CI, 1.32 to 2.72) compared with patients who experienced a postoperative decrease in either filtration marker. Patients who had simultaneous elevations of 25% or higher in cystatin C and creatinine were at similar adjusted risk for 3-year mortality (HR, 1.79; 95% CI, 1.03 to 3.1) as those with a 25% or higher increase in cystatin C alone (HR, 2.2; 95% CI, 1.09 to 4.47). Elevations in creatinine postoperatively are more common than elevations in cystatin C. However, elevations in cystatin C appeared to be associated with a higher risk of death after hospital discharge.

Serum cystatin C levels are associated with asymptomatic peripheral arterial disease in type 2 diabetes mellitus patients without overt nephropathy

AimsWe investigated the association between serum cystatin C and asymptomatic peripheral artery disease (PAD) in type 2 diabetes mellitus patients with normal renal function or mild renal impairment and we compared cystatin C with albuminuria and estimated glomerular filtration rate (eGFR) for prediction of PAD. MethodsWe enrolled 272 patients with type 2 diabetes. Patients were excluded if they had an eGFR<60mL/min per 1.73m2, 24-h urine albumin (24h-uAlb)≥300mg/day, serum creatinine (Cr)>1.3mg/dL, or previous history of cardiovascular disease. PAD was defined as having an ankle brachial index (ABI)≤0.9. ResultsPatients with PAD were more likely to have a lower eGFR and higher values of 24h-uAlb, cystatin C, and serum Cr than subjects without PAD. Cystatin C was independently associated with age, current smoking, HDL, eGFR, and PAD. Odds ratios (ORs) for PAD after adjustment for age, gender, smoking, and hypertension were 1.71 (95% CI, 1.02–2.85), 1.51 (95% CI, 0.93–2.44), and 0.78 (95% CI, 0.41–1.49) for a one standard deviation increase in cystatin C, 24h-uAlb, and eGFR, respectively. ConclusionsCystatin C was independently associated with PAD in type 2 diabetes mellitus patients without overt nephropathy.

Sepsis-induced acute kidney injury by standardized colon ascendens stent peritonitis in rats - a simple, reproducible animal model.

BackgroundUp to 50% of septic patients develop acute kidney injury (AKI). The pathomechanism of septic AKI is poorly understood. Therefore, we established an innovative rodent model to characterize sepsis-induced AKI by standardized colon ascendens stent peritonitis (sCASP). The model has a standardized focus of infection, an intensive care set up with monitoring of haemodynamics and oxygenation resulting in predictable impairment of renal function, AKI parameters as well as histopathology scoring.MethodsAnaesthetized rats underwent the sCASP procedure, whereas sham animals were sham operated and control animals were just monitored invasively. Haemodynamic variables and blood gases were continuously measured. After 24 h, animals were reanesthetized; cardiac output (CO), inulin and PAH clearances were measured and later on kidneys were harvested; and creatinine, urea, cystatin C and neutrophil gelatinase-associated lipocalin (NGAL) were analysed. Additional sCASP-treated animals were investigated after 3 and 9 days.ResultsAll sCASP-treated animals survived, whilst ubiquitous peritonitis and significantly deteriorated clinical and macrohaemodynamic sepsis signs after 24 h (MAP, CO, heart rate) were obvious. Blood analyses showed increased lactate and IL-6 levels as well as leucopenia. Urine output, inulin and PAH clearance were significantly decreased in sCASP compared to sham and control. Additionally, significant increase in cystatin C and NGAL was detected. Standard parameters like serum creatinine and urea were elevated and sCASP-induced sepsis increased significantly in a time-dependent manner. The renal histopathological score of sCASP-treated animals deteriorated after 3 and 9 days.ConclusionsThe presented sCASP method is a standardized, reliable and reproducible method to induce septic AKI. The intensive care set up, continuous macrohaemodynamic and gas exchange monitoring, low mortality rate as well as the opportunity of detailed analyses of kidney function and impairments are advantages of this setup. Thus, our described method may serve as a new standard for experimental investigations of septic AKI.

Urinary exosomes: a novel means to non-invasively assess changes in renal gene and protein expression.

BackgroundIn clinical practice, there is a lack of markers for the non-invasive diagnosis and follow-up of kidney disease. Exosomes are membrane vesicles, which are secreted from their cells of origin into surrounding body fluids and contain proteins and mRNA which are protected from digestive enzymes by a cell membrane.MethodsToxic podocyte damage was induced by puromycin aminonucleoside in rats (PAN). Urinary exosomes were isolated by ultracentrifugation at different time points during the disease. Exosomal mRNA was isolated, amplified, and the mRNA species were globally assessed by gene array analysis. Tissue-specific gene and protein expression was assessed by RT-qPCR analysis and immunohistochemistry.ResultsGene array analysis of mRNA isolated from urinary exosomes revealed cystatin C mRNA as one of the most highly regulated genes. Its gene expression increased 7.5-fold by day 5 and remained high with a 1.9-fold increase until day 10. This was paralleled by a 2-fold increase in cystatin C mRNA expression in the renal cortex. Protein expression in the kidneys also dramatically increased with de novo expression of cystatin C in glomerular podocytes in parts of the proximal tubule and the renal medulla. Urinary excretion of cystatin C increased approximately 2-fold.ConclusionIn this proof-of-concept study, we could demonstrate that changes in urinary exosomal cystatin C mRNA expression are representative of changes in renal mRNA and protein expression. Because cells lining the urinary tract produce urinary exosomal cystatin C mRNA, it might be a more specific marker of renal damage than glomerular-filtered free cystatin C.

Clinical Utility of Serum Cystatin C in Predicting Coronary Artery Disease in Patients Without Chronic Kidney Disease

BackgroundCystatin C has been proposed as a novel marker of renal function and predictor of cardiovascular risk. The aim of this study was to investigate the role of cystatin C level as a predictor of cardiovascular events in patients with coronary artery disease (CAD).MethodsThree hundred and five coronary artery patients were included in this study. Serum cystatin C levels, high‐sensitive C‐reactive protein (hs‐CRP), and oxidative stress were measured. Estimated glomerular filtration rate (eGFR) and the CAD severity score were calculated.ResultsCystatin C was correlated with the CAD severity score (r = 0.631, P < 0.0001) and was significantly elevated in the CAD severity score >50. Every 0.1 mg/l increase in cystatin C, 2 mg/l increase in hs‐CRP, 0.2 mmol/l decrease in high‐density lipoprotein cholesterol, 13.7 ml/min decrease in eGFR, and 1.51 μmol/l increase in homocysteine caused a 34, 12, 5, and 22% increase in the risk of having CAD, respectively.ConclusionCystatin C could be a useful laboratory biochemical marker in predicting the severity of CAD. Cystatin C is associated with biochemical atherosclerosis markers such as CRP and homocysteine.

Human cystatin C: A new biomarker of idiopathic pulmonary fibrosis?

Human idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disorder with a poor prognosis. The identification of a new and specific biomarker in bronchoalveolar lavage fluids (BALFs) may assist in the diagnosis of the disease. Characterization of cysteine Cats and their endogenous inhibitor, cystatin C, was conducted by immunochemical analysis and measurement of endopeptidase activity of control (n = 11) and IPF (n = 25) BALFs (normalized conditions, 20 μg protein/assay). Cathepsin (Cat) B was detected as proform and mature enzyme for both control and IPF samples, while Cats K, L, and S were found as zymogens with a strengthened staining in IPF BALFs. The overall endopeptidase activity related mainly to Cat B and did not vary significantly between control and IPF samples. Conversely a significant increase of immunoreactive cystatin C was measured in BALFs for each of three IPF grades. An excessive deposition of extracellular matrix proteins is the hallmark of fibrotic disorders. Cats are potent collagenases and might be essential for lung homeostasis. Taken together, increase of cystatin C in IPF BALFs may reflect abnormal regulation of proteolytic activity of Cats in lung, which in turn can promote the development of fibrosis.

Influence of Arterial Stiffness on the Progression of Chronic Kidney Disease Over a 1-year Period

Recent studies demonstrated that progression of chronic kidney disease (CKD) over a 1-year period is associated with a substantially increased risk of mortality. Cystatin C has emerged as a reliable marker of kidney function. In this study, we evaluated the factors associated with increase in cystatin C over a 1-year period in patients with cardiovascular disease.

Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

The amyloid precursor protein (APP) is well studied for its role in Alzheimer disease. However, little is known about its normal function. In this study, we examined the role of APP in neural stem/progenitor cell (NSPC) proliferation. NSPCs derived from APP-overexpressing Tg2576 transgenic mice proliferated more rapidly than NSPCs from the corresponding background strain (C57Bl/6xSJL) wild-type mice. In contrast, NSPCs from APP knock-out (APP-KO) mice had reduced proliferation rates when compared with NSPCs from the corresponding background strain (C57Bl/6). A secreted factor, identified as cystatin C, was found to be responsible for this effect. Levels of cystatin C were higher in the Tg2576 conditioned medium and lower in the APP-KO conditioned medium. Furthermore, immunodepletion of cystatin C from the conditioned medium completely removed the ability of the conditioned medium to increase NSPC proliferation. The results demonstrate that APP expression stimulates NSPC proliferation and that this effect is mediated via an increase in cystatin C secretion.

Cathepsin B and cystatin B in HIV-seropositive women are associated with infection and HIV-1-associated neurocognitive disorders

HIV-1-associated neurocognitive disorders (HAND) is triggered by immune activation of brain cells and remain prevalent during progressive viral infection despite antiretroviral therapy. Cathepsins and cystatins are lysosomal proteins secreted by macrophages and microglia, and may play important roles in neuroregulatory responses. Our laboratory has shown increased secretion and neurotoxicity of cathepsin B from in-vitro HIV-infected monocyte-derived macrophages, and increased expression in postmortem brain tissue with HIV encephalitis and HAND. We hypothesized that cystatin B and cathepsin B could represent potential biomarkers for HAND. Monocytes, plasma, and cerebrospinal fluid (CSF) from retrospective samples from 63 HIV-seropositive Hispanic women were selected for this study. These were stratified as 27 normal, 14 asymptomatic, and 22 HIV dementia, and as 14 progressors and 17 nonprogressors. Samples were evaluated for cystatins B and C and cathepsin B expression and activity. Increased cathepsin B and cystatins B and C were found in plasma of HIV-seropositive women. Higher intracellular expression of cathepsin B and cystatin B were found in monocytes from women with HIV-associated dementia (P < 0.05). Significant increase in cystatin B concentration in CSF was found in women with dementia compared with HIV-seropositive asymptomatic women. These results demonstrate that dysregulation of cystatin B-cathepsin B system is operative in HIV-associated neurocognitive impairment and suggests that intracellular expression of cystatin B and cathepsin B in monocytes could be potential candidate biomarkers for HIV dementia, whereas increased cathepsin B and cystatins B and C in plasma are potential candidate markers of chronic HIV-1 activation.

Serum Cystatin C– Versus Creatinine-Based Definitions of Acute Kidney Injury Following Cardiac Surgery: A Prospective Cohort Study

The primary aim of this study was to compare the sensitivity and rapidity of acute kidney injury (AKI) detection by cystatin C level relative to creatinine level after cardiac surgery. Prospective cohort study. 1,150 high-risk adult cardiac surgery patients in the TRIBE-AKI (Translational Research Investigating Biomarker Endpoints for Acute Kidney Injury) Consortium. Changes in serum creatinine and cystatin C levels. Postsurgical incidence of AKI. Serum creatinine and cystatin C were measured at the preoperative visit and daily on postoperative days 1-5. To allow comparisons between changes in creatinine and cystatin C levels, AKI end points were defined by the relative increases in each marker from baseline (25%, 50%, and 100%) and the incidence of AKI was compared based on each marker. Secondary aims were to compare clinical outcomes among patients defined as having AKI by cystatin C and/or creatinine levels. Overall, serum creatinine level detected more cases of AKI than cystatin C level: 35% developed a ≥25% increase in serum creatinine level, whereas only 23% had a ≥25% increase in cystatin C level (P < 0.001). Creatinine level also had higher proportions meeting the 50% (14% and 8%; P < 0.001) and 100% (4% and 2%; P = 0.005) thresholds for AKI diagnosis. Clinical outcomes generally were not statistically different for AKI cases detected by creatinine or cystatin C level. However, for each AKI threshold, patients with AKI confirmed by both markers had a significantly higher risk of the combined mortality/dialysis outcome compared with patients with AKI detected by creatinine level alone (P = 0.002). There were few adverse clinical outcomes, limiting our ability to detect differences in outcomes between subgroups of patients based on their definitions of AKI. In this large multicenter study, we found that cystatin C level was less sensitive for AKI detection than creatinine level. However, confirmation by cystatin C level appeared to identify a subset of patients with AKI with a substantially higher risk of adverse outcomes.

Impact of Cystatin C and RIFLE on Renal Function Assessment After Cardiac Surgery

The lack of a consensus classification system and of a specific, sensitive, and early-stage biomarker for kidney injury frequently results in late diagnosis of acute kidney injury (AKI). The aim of the present study was to characterize the discriminatory power of cystatin C and the RIFLE and Acute Kidney Injury Network (AKIN) criteria for the assessment of renal dysfunction after cardiac surgery. A longitudinal, quantitative study was conducted in intensive care units of the Heart Institute (São Paulo, Brazil) in which 121 patients were followed for the first 72 hr after cardiac surgery. Most of the patients were male (61.2%), and the mean age was 50 years. The most frequent surgeries were valve replacement (48.8%) and myocardial revascularization (43.8%). AKI was defined as an increase of at least 50%, 0.3 mg/dl or 0.5 mg/dl in baseline serum creatinine. The percentage of participants meeting each of these criteria was 13.2%, 28.1%, and 11.6%, respectively. A progressive increase in cystatin C levels was associated with a worsening of renal function, as classified by RIFLE and AKIN (p < .05). Analysis of the receiver operating characteristic (ROC) curves showed the RIFLE and AKIN classification to have good discriminatory power for the assessment of renal function, with the performance of cystatin C being poorer (area under the curve: 0.804 and 0.794 vs. 0.719). However, combining cystatin C and RIFLE resulted in greater discriminatory power for detecting kidney injury in postoperative patients than any marker in isolation.

Fenofibrate-Associated Creatinine Increase: A Case for More Prospective Studies

We read with interest a recently published study by Abbas et al in which the authors discussed the factors associated with the well-established rise in creatinine associated with fibrate treatment. They retrospectively analysed the case notes from a lipid clinic database of 132 patients [1]. In accord with a number of studies published in the last 13 years (Tsimihodimos et al [2], Hottelart et al [3], Ansquer et al [4] ), interalia, the authors have shown a fibrate-associated increase in creatinine. In a recent prospective study, in hyperlipidaemic patients attending a lipid clinic [5] we have demonstrated a similar rise in serum creatinine using a Siemens enzymatic creatinine assay (Siemens Healthcare Diagnostics, Frimley, UK), which is traceable to isotope dilution/ mass spectrometry (ID/MS). This rise in creatinine (median 15.1%; range 5.5-23.2 %) was accompanied by an increase in cystatin C (median 9.9%; range 1.1-26.1%) in 10 of the 12 patients studied. We concluded that since the increase in serum creatinine concentration was accompanied by a rise in cystatin C, an independent marker of GFR, the fibrate-related creatinine increase reflects a genuine reduction in renal function rather than an increased metabolic production of creatinine as previously proposed by Hottelart et al [3]. It is unlikely that another mechanism is responsible since it would need to affect both creatinine and cystatin C in a similar manner. Although our study was limited to only 12 patients, our findings reflect those of larger studies, for example, a substudy of the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial [6]. Recently, Mychaleckj et al [7] have shown a reversal of the fibrate-induced rise in cystatin C concentration on stopping fibrate treatment, which further suggests that fibrateinduced renal hypofunction occurs. In the study by Abbas et al [1] the use of a Jaffe creatinine assay presents a potential problem, since, unlike the enzymatic method used in our study, this method is prone to a range of analytical interferences. The findings, however, are still of interest. Although the dose of fenofibrate used was not stated, (and was probably variable), the authors have interestingly, corrected their data for the duration of treatment. We speculate that some of the differences seen between studies may be related to fenofibrate dose in addition to the duration of therapy. There is a need for more prospective studies investigating the mechanism(s) and clinical significance of a fibrate-associated creatinine increase. The measurement of GFR using more accurate methods such as Inulin or para amino hippurate (PAH) clearance do not lend themselves to routine clinical use, but may currently offer the best prospect for gaining a clearer insight into this interesting phenomenon.

Cystatin C as risk factor for cardiovascular events and all-cause mortality in the general population. The Tromsø Study

Glomerular filtration rate<60 mL/min/1.73 m2 is associated with increased cardiovascular risk. Cystatin C is believed to be a better tool than creatinine for detection of mild renal dysfunction (>60 mL/min/1.73 m2) and possibly a more sensitive marker for cardiovascular risk and all-cause mortality. We examined the association of cystatin C with cardiovascular morbidity and all-cause mortality in a prospective population-based study. Cystatin C was measured in 2852 men and 3153 women in the Tromsø Study 1994/95. Gender-specific associations during 12 years of follow-up for all-cause mortality and 9.5 years for myocardial infarction (MI) and ischaemic stroke were assessed (Cox proportional hazard ratios, HRs). During follow-up, 591 MIs, 293 ischaemic strokes and 1262 deaths occurred. In women, HR for all-cause mortality was increased in the upper cystatin C quartile (≥0.93 mg/L) compared with the lowest quartile (≤0.73 mg/L); 1.38, 95% confidence interval 1.04-1.84. A significant interaction with gender was observed. One SD (0.17 mg/L) increase in cystatin C was associated with 9% higher risk of death in women, also when persons with a cancer history were excluded. Crude HRs for MI and ischaemic stroke were increased in both genders, but the associations did not persist after multivariable adjustments. No independent associations with end points were observed in non-gender-specific analyses. Cystatin C was not independently associated with fatal and non-fatal MI or ischaemic stroke in the general population. However, cystatin C was a risk factor for all-cause mortality in women.

Predictors of worsening renal function after computed tomography coronary angiography: Assessed by cystatin C

An increase in cystatin C (CyC) of ≥10% for 24 hours may predict contrast-induced nephropathy and worse outcomes in patients with renal dysfunction undergoing invasive coronary angiography. We investigated the changes in CyC in patients with preserved renal function referred for contrast-enhanced coronary computed tomography angiography (CTA). We studied 151 patients undergoing CTA with 70 mL of iopamidol. Serum creatinine and CyC, a sensitive measure of renal dysfunction, shown to be associated with adverse outcomes, were measured 1 day and 1 week after CTA, respectively. The percentage change in CyC (%CyC) was determined and evaluated in comparison to fluid intake. The patients were dichotomized into 2 groups: 47 patients had ≥10% increase in CyC 1 day after CTA (group A) and 104 did not (group B). The percentage of diabetic patients, hemoglobin A1c (HbA1c), and the CyC levels at 1 week were significantly greater, and the oral fluid volume was significantly lower in group A than in group B. The %CyC inversely correlated with oral fluid volume (r = -0.80, P < 0.0001) and positively with HbA1c (r = 0.38, P < 0.001). Multiple regression analysis showed that oral fluid intake (β = -0.796, P < 0.0001) and HbA1c (β = 0.128, P=0.007) are independent predictors for %CyC of ≥10%. Frequency of CyC elevation was strongly related to hydration after the study and also weakly related to HbA1c. Sufficient oral fluid intake (oral fluid volume/kg ≥ 20 mL/kg) is crucial, particularly for poorly controlled diabetic patients referred for CTA even though they show preserved renal function.

Cystatin C as a Biomarker of Worsening Renal Function in Acute Heart Failure: Insights from the DOSE Study

The definition of worsening renal function (WRF) varies according to source and no clear consensus exists as to the preferred biomarker to evaluate WRF. Cystatin C has emerged as a novel marker of renal function. An increase in cystatin C >0.3 mg/L has been associated with worse short term prognosis.

Renal function and nonvertebral fracture risk in multiethnic women: the Women’s Health Initiative (WHI)

To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women's Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups. The purpose of this study was to determine whether renal function is associated with fracture risk within racial/ethnic groups. A nested case-control study was conducted among 93,673 postmenopausal women; incident nonvertebral fractures were identified in 362 Black, 183 Hispanic, 110 Asian, and 45 American-Indian women. A random sample of 395 White women with incident nonvertebral fracture was chosen. One nonfracture control for each case was selected (matched on age, race/ethnicity, and blood draw date). Cystatin C levels were measured using baseline serum, and estimated glomerular filtration rate calculated (eGFR(cys-c)). Each 1 SD increase in cystatin C was associated with a 1.2-fold increased risk of fracture among White women (adjusted odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.04-1.46). The OR of fracture was 1.16 (95% CI, 0.85-1.58) among women with eGFR(cys-c) 60-90 mL/min/1.73 m(2) and 2.46 (95% CI, 1.16-5.21) among those with eGFR(cys-c) <60 mL/min/1.73 m(2) compared to the reference group (eGFR(cys-c) >90 mL/min/1.73 m(2)) (p trend = 0.05). The association was reduced after adjustment for cytokine TNFα soluble receptors (OR, 1.62; 95% CI, 0.59-4.46 for eGFR(cys-c) <60 mL/min/1.73 m(2)). Among Blacks, there was an association between cystatin C and fracture risk (OR per 1 SD increase, 1.15; 95% CI, 1.00-1.32); after adjustment, this association was only modestly attenuated, but no longer statistically significant. There was no evidence of significant associations among Hispanic, Asian, or American-Indian women. Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture. Effects of renal function on chronic inflammation may mediate this association. Reduced renal function may increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.

Effect of prolonged standardized bed rest on cystatin C and other markers of cardiovascular risk

BackgroundSedentary lifestyle is associated with coronary artery disease but even shorter periods of physical inactivity may increase cardiovascular risk. Cystatin C is independently associated with cardiovascular disease and our objective was to investigate the relation between this novel biomarker and standardized bed rest. Research of immobilization physiology in humans is challenging because good biological models are in short supply. From the Women International Space simulation for Exploration study (WISE) we studied markers of atherosclerosis and kidney function, including cystatin C, in a standardized bed rest study on healthy volunteers. Fifteen healthy female volunteers participated in a 20-day ambulatory control period followed by 60 days of bed rest in head-down tilt position (-6°) 24 h a day, finalized by 20 days of recovery. The subjects were randomized into two groups during bed rest: a control group (n = 8) that remained physically inactive and an exercise group (n = 7) that participated in both supine resistance and aerobic exercise training.ResultsCompared to baseline values there was a statistically significant increase in cystatin C in both groups after bed rest (P < 0.001). Glomerular filtration rate (GFR), calculated by both cystatin C and Cockcroft-Gault equation, decreased after bed rest while there were no differences in creatinine or creatine kinase levels. CRP did not change during bed rest in the exercise group, but there was an increase of CRP in the control group during recovery compared to both the baseline and the bed rest periods. The apo-B/apo-Ai ratio increased during bed rest and decreased again in the recovery period. Subjects experienced a small but statistically significant reduction in weight during bed rest and compared to baseline weights remained lower at day 8 of recovery.ConclusionDuring and following prolonged standardized bed rest the concentrations of several clinically relevant cardiovascular risk markers change.

Cystatine C et risque cardiovasculaire

Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular disease (CVD) and cardiovascular events. Cystatin C, a protease inhibitor synthesized in all nucleated cells, has been proposed as a replacement for serum creatinine for the assessment of renal function, particularly to detect small reductions in glomerular filtration rate. This report presents a review of the role of cystatin C as a predictor of cardiovascularis. Patients with higher circulating cystatin C concentrations appear to have an increased cardiovascular risk profile, i.e., they are older and have a higher prevalence of systemic hypertension, dyslipidemia, documented CVD, increased body mass index, and increased concentrations of C-reactive protein. Prospective studies have shown, in various clinical scenarios, that patients with increased cystatin C are at a higher risk of developing both CVD and CKD. Importantly, cystatin C appears to be a useful marker or identifying individuals at a higher risk of cardiovascular events among patients belonging ot a relatively lox-risk category as assessed by both creatinine and estimated glomerular filtration rate values. Of interest, elastolytic proteases and their inhibitors, in particular cystatin C, have been shown to be directly involved in the atherosclerotic process. Increases concentrations of cystatin C appear to be indicative of preclinical kidney disease associated with adverse outcomes. Clinical studies involving direct glomerular filtration rate measurements are required to ascertain both the true role of this promising marker in renal disease and whether atherogenic factors like inflammation can account for increases in cystatin C concentrations, thus explaining its predictive value in CVD.