Urinary Biomarkers and Risk of ESRD in the Atherosclerosis Risk in Communities Study

Background and objectives

Liver fatty acid binding protein (L-FABP), kidney injury molecule 1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), and neutrophil gelatinase–associated lipocalin (NGAL) are urinary markers of tubular injury that may also be markers of chronic kidney damage. We evaluated the association of these markers with incident ESRD in a community-based sample from the Atherosclerosis Risk in Communities Study.

Design, setting, participants, & measurements

This was a matched case-control study of 135 patients with ESRD and 186 controls who were matched on sex, race, kidney function, and diabetes status at baseline (Atherosclerosis Risk in Communities Study visit 4, 1996–1998). Urinary KIM-1 indexed to creatinine (Cr), NAG/Cr, NGAL/Cr, and L-FABP/Cr were measured in stored spot urine samples from the baseline examination. Associations of KIM-1/Cr, NAG/Cr, and NGAL/Cr with patients with incident ESRD through 2008 were modeled continuously and categorically (quartiles) using conditional logistic regression. L-FABP/Cr was modeled only categorically because of a large number of measurements below the lower limit of detection for the assay (2.4 ng/ml).

Results

No significant associations were observed for NAG/Cr, NGAL/Cr, or L-FABP/Cr with ESRD. Those in the highest category for KIM-1/Cr had a higher risk of ESRD compared with those with undetectable biomarker levels (reference group) in unadjusted models (odds ratio, 2.24; 95% confidence interval, 1.97 to 4.69; P=0.03) or adjustment for age (odds ratio, 2.23; 95% confidence interval, 1.06 to 4.67; P=0.03). This association was attenuated with additional adjustment for baseline kidney function (odds ratio, 2.02; 95% confidence interval, 0.95 to 4.31; P=0.07 after additional adjustment for eGFR and natural log of the urinary albumin-to-creatinine ratio). No association between KIM-1/Cr and ESRD was found when KIM-1/Cr was analyzed as a continuous variable.

Conclusions

Elevated urinary KIM-1/Cr may be associated with a higher risk of incident ESRD, but it does not add to risk prediction after accounting for traditional markers of kidney function in this population.     

Clinical Significance of Urinary Biomarkers in Patients With Primary Focal Segmental Glomerulosclerosis

Background

Focal segmental glomerulosclerosis (FSGS) is often accompanied with tubulointerstitial lesion. This study aimed to assess the role of urinary biomarkers in predicting tubulointerstitial lesion and treatment response in FSGS patients.

Urinary tubular biomarkers in short-term type 2 diabetes mellitus patients: a cross-sectional study

The purpose of this study was to investigate the prevalence of tubular damage in short-term (less than five years) type 2 diabetes mellitus (T2DM) patients and to explore the correlation between tubular markers and their relationship with renal indices at different stages of diabetic nephropathy. A group of 101 short-term T2DM patients and 28 control subjects were recruited. Tubular markers, such as neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D: -glucosaminidase (NAG), and kidney injury molecule 1 (KIM-1), as well as urinary albumin excretion were measured in voided urine. Glomerular filtration rate (GFR) was estimated via Macisaac's formula. The patients were further categorized into three groups, namely, the normoalbuminuria, microalbuminuria, and macroalbuminuria groups, according to their urine albumin/creatinine ratio (UACR). Urinary tubular markers were compared and their correlations with renal indices [UACR and estimated GFR (eGFR)] were analyzed among the different diabetic groups. Compared with the control group, Urinary NGAL [median (IQR)][83.6(41.4-138.7) μg/gcr vs. 32.9(26.1-64.5) μg/gcr], NAG [13.5(8.7-17.9) U/gcr vs. 7.6(6.5-13.0) U/gcr] and KIM-1 [120.0(98.4-139.9) ng/gcr vs. 103.1(86.8-106.2) ng/gcr] in the T2DM were all markedly increased. For all patients, urinary NGAL had stronger positive correlations with UACR than NAG (R = 0.556 vs. 0.305, both P < 0.05). In addition, only urinary NGAL showed a negative correlation with eGFR (R = -0.215, P < 0.05). Urinary KIM-1, however, showed no significant difference among the three T2DM groups and did not correlate with either UACR or eGFR. As UACR increased from the normoalbuminuria to the last macroalbuminuria group, all of the markers increased. However, only the concentrations of NGAL were statistically different among the three diabetic groups. The correlation between the tubular markers and their relationships with the renal indices differed markedly among the three T2DM groups. In conclusion, these results suggest that tubular damage is common in short-term T2DM patients. Urinary NGAL may be a promising early marker for monitoring renal impairment in short-term T2DM patients.     

Urinary Biomarkers in the Early Detection of Acute Kidney Injury after Cardiac Surgery

Background and objectives: Serum creatinine (Scr) does not allow for early diagnosis of acute kidney injury (AKI). The diagnostic utility of urinary kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and neutrophil gelatinase associated lipocalin (NGAL) was evaluated for the early detection of postoperative AKI in a prospective study of 90 adults undergoing cardiac surgery.Designs, setting, participants, & measurements: Urinary KIM-1, NAG, and NGAL were measured at 5 time points for the first 24 h after operation and normalized to the urinary creatinine concentration after cardiac surgery. Receiver-operating characteristic curves were generated and the areas under the curve (AUCs) compared for performance of biomarkers in detection of postoperative AKI.Results: Thirty-six patients developed AKI, defined as an increase in Scr of ≥0.3 mg/dl within 72 h after surgery. The AUCs for KIM-1 to predict AKI immediately and 3 h after operation were 0.68 and 0.65; 0.61 and 0.63 for NAG; and 0.59 and 0.65 for NGAL, respectively. Combining the three biomarkers enhanced the sensitivity of early detection of postoperative AKI compared with individual biomarkers: the AUCs for the three biomarkers combined were 0.75 and 0.78. The performance of combining biomarkers was even better among 16 early postoperative AKI patients with AUCs of 0.80 and 0.84, respectively.Conclusions: The results of this study support that a combination of urinary biomarkers may allow for early detection of postoperative AKI after cardiac surgery before a rise in Scr.Acute kidney injury (AKI) is an important cause of morbidity and mortality in hospitalized patients (1). The incidence of hospital-acquired AKI varies from 5% in patients with normal preoperative renal function to 25% in intensive care unit (ICU) patients (2–4). Mortality rates of patients with postoperative AKI range from 40 to 60% among ICU patients who require a renal replacement therapy (5–7). Dialysis remains the only U.S. Food and Drug Administration approved treatment option for established AKI.Recently, two new definitions of AKI have been developed: RIFLE (risk, injury, failure, loss, and ESRD) and AKIN (acute kidney injury network) criteria (8,9). It is, however, a challenge to detect AKI in a timely fashion with current RIFLE and AKIN criteria because these definitions are entirely based on increases of serum creatinine (Scr) or decreases of urine output. Scr is insensitive for the early detection of AKI because the change in Scr does not discriminate the time and type of renal insult or the site and extent of glomerular or tubular injury (8,10).Several proteins and biochemical markers emerged as sensitive and specific biomarkers capable of detecting acute tubular injury early and proved to be promising biomarkers as indicators of AKI in recent human studies (11,12). These include N-acetyl-β-D-glucosaminidase (NAG), neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, and IL-18 (13–25). However, there are no previously reported data for the temporal expression pattern of urinary KIM-1 and NAG before the development of AKI in adult patients. In addition, there is a large discrepancy in the performance of NGAL as an early AKI marker between adult and pediatric AKI patients (15,17,19,20). Furthermore, there are few data on the influence of prolonged duration of storage at −80°C and the number of freeze-thaw cycles on stability of urinary biomarkers at the present time, which will be critical to ongoing validation studies of potential tandem AKI biomarkers (26).In this study, we studied the diagnostic utility of urinary KIM-1, NAG, and NGAL as biomarkers separately and in combination for the early detection of postoperative AKI and the temporal expression patterns of urinary biomarkers before the development of postoperative AKI in patients undergoing cardiac surgery. In addition, the stability of urinary KIM-1, NAG, and NGAL were tested with various handling and storing conditions to evaluate the accuracy of the biomarker measurement because our prospective collected urine samples were frozen at −80°C for 1 yr and were subjected to at least two freeze-thaw cycles before measurement for KIM-1 and NAG.     

Neutrophil gelatinase-associated lipocalin levels in isolated coronary artery ectasia

Background

The pathophysiology of coronary artery ectasia (CAE) is still unknown. Inflammation and degradation of connective tissue may have a role in the development of coronary ectasia. In the present study, the authors examined neutrophil gelatinase-associated lipocalin (NGAL) levels in isolated CAE patients.

Methods

Thirty-five patients with isolated CAE (25 males; mean age, 59 ± 10 years) and 35 age- and sex-matched healty volunteers (22 males; mean age, 57 ± 11 years) who had been shown to have normal coronary arteries were included in the study. Basal characteristics were recorded. Serum NGAL levels were determined with an enzyme-linked immunosorbent assay kit.

Results

NGAL levels were significantly higher in the isolated CAE group than in the control group (65.1 ± 13 vs 53.7 ± 19 ng/mL; P = 0.006). There were also significant difference in NGAL levels according to the number of ectatic coronary arteries (58.1 ± 13, 70.9 ± 9, and 71.1 ± 11 ng/mL for 1, 2, and 3 arteries, respectively; P = 0.015). Level of NGAL was lowest in patients who have only 1 ectatic coronary artery.

Conclusion

Serum NGAL levels increased in patients with isolated CAE, and NGAL may play a crucial role in the development and/or progression of coronary artery ectasia.     

Time of injury affects urinary biomarker predictive values for acute kidney injury in critically ill,non-septic patients

Background

The predictive value of acute kidney injury (AKI) urinary biomarkers may depend on the time interval following tubular injury, thereby explaining in part the heterogeneous performance of these markers that has been reported in the literature. We studied the influence of timing on the predictive values of tubular proteins, measured before the rise of serum creatinine (SCr) in critically ill, non-septic patients.

Methods

Seven hundred adult critically ill patients were prospectively included for urine measurements at four time-points prior to the rise in serum creatinine (T?=?0, -16, -20 and -24 h). Patients with sepsis and or AKI at ICU entry were excluded. The urinary excretion of the proteins, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), which are up-regulated in the distal and proximal tubules, respectively, were measured as well as the constitutive cytoplasmatic enzymes, π- and α-glutathione-S-transferase (GST), which are released by the distal and proximal tubules, respectively.

Results

Five hundred and forty-three subjects were eligible for further analyses; however, 49 developed AKI in the first 48 h. Both NGAL (P?=?0.001 at T?=?-24 vs. non-AKI patients) and KIM-1 (P?<?0.0001 at T?=?0 vs. non-AKI patients) concentrations gradually increased until AKI diagnosis, whereas π- and α-GST peaked at T?=?-24 before AKI (P?=?0.006 and P?=?0.002, respectively vs. non-AKI patients) and showed a rapid decline afterwards. The predictive values at T?=?-24 prior to AKI were modest for π- and α-GST, whereas NGAL sufficiently predicted AKI at T?=?-24 and its predictive power improved as the time interval to AKI presentation decreased (area under the receiver operating characteristic curve; AUC?=?0.79, P?<?0.0001). KIM-1 was a good discriminator at T?=?0 only (AUC?=?0.73, P?<?0.0001).

Conclusions

NGAL, KIM-1, pi- and alpha-GST displayed unique and mutually incomparable time dependent characteristics during the development of non-sepsis related AKI. Therefore, the time-relationship between the biomarker measurements and the injurious event influences the individual test results.

     

Level of serum IL-12 and its correlation with endothelial dysfunction, insulin resistance, proinflammatory cytokines and lipid profile in newly diagnosed type 2 diabetes

Aim

This study was an attempt to evaluate and correlate serum interleukin-12 (IL-12) with different circulating markers in newly diagnosed type-2 diabetes mellitus (T2DM) for possible progression of atherosclerosis.

Methods

For this study, we recruited 1968 family members of diabetics and 349 had abnormal glucose. Out of 349 subjects, 197 were T2DM as per American Diabetes Association guidelines and further investigated for cardiovascular abnormalities. 63 T2DM have high sensitive C-reactive protein (hsCRP) > 3.0 mg/l and cardiovascular complications. Overall, 150 subjects, 50 healthy, 50 T2DM (D1) and 50 T2DM with cardiovascular complications (D2) were enrolled and investigated for soluble markers.

Results

The levels of serum glucose, proinflammatory cytokines (IL-6, IL-12, tumor necrosis factor), endothelial dysfunction markers [vascular cell adhesion molecule-1 (VCAM-1), inter-cellular adhesion molecule-1 (ICAM-1), nitric oxide] and lipid abnormality were highest in D2 group. Correlation and regression study showed that IL-12 was dependent on hsCRP, insulin resistance, VCAM-1, ICAM-1 and lipids. The multivariate stepwise regression analysis demonstrates that hsCRP contributes significantly for variance of IL-12.

Conclusion

This study reveals that, even first-time diagnosis of T2DM, subjects with higher insulin resistance and abnormal lipids have elevated IL-12, endothelial dysfunction and proinflammatory markers. Further increased hsCRP enhance IL-12 which up-regulate cardiovascular disease progression.     

Polyol profile as an early diagnostic and prognostic marker in natural product chemoprevention of hepatocellular carcinoma in diabetic rats

Aim

Diabetes mellitus (DM) is a risk factor for hepatocellular carcinoma (HCC). It directs glucose to sorbitol and fructose in polyol pathway (PP). To pursue contribution of PP in hepatocarcinogenesis.

Methods

We utilized ascorbic acid (AA) and diallyl sulfide (DAS) in experimental DM and HCC against control. HCC was induced by diethyl nitrosamine (DENA, one intraperitoneal (IP) dose 125 mg/kg), DM, by streptozotocin (STZ, IP dose 65 mg/kg). AA was given as 7.4 g/kg/d, I.P., DAS 200 mg/kg/d, orally. All animals were killed after 10 weeks.

Results

DENA elevated serum AFP, erythrocyte sorbitol (ES), neoplastic changes in liver, lowered blood glucose, increased hepatocyte aldose reductase (AR) and sorbitol dehydrogenase (SDH), significantly alleviated by DAS/AA combination. DM elevated ES activating AR, inhibiting SDH, improved by DAS and AA.

Conclusion

Co-induction of DM and HCC increased liver tissue lesion, serum AFP, ES, liver AR and SDH. Co-administration of DAS/AA reduced ES, AR without changing SDH. DAS/AA co-therapy lowered ES by depressing AR without affecting SDH, meaning that AR is activated by cancer and DM in different ways. PP is early marker for HCC detection and response to chemoprevention. DAS/AA combination is promising cost effective chemopreventive and anti-diabetic combination.     

Relationship between oxidative stress and apoptotic markers in lymphocytes of diabetic patients with chronic non healing wound

Aims

Hyperglycemia causes generation of free radicals which leads to oxidative stress and apoptosis in various cells. The present study was undertaken to investigate the correlation between oxidative stress and apoptotic markers in lymphocytes of diabetic patients with chronic non healing wounds.

Methods

Thirty healthy, thirty uncontrolled type 2 diabetes mellitus (T2DM) and thirty uncontrolled T2DM with chronic, non healing, neuropathic diabetic foot patients were included in this study. Indices of oxidative stress inside the lymphocyte lysate were estimated by measuring content of superoxide dismutase (SOD), Catalase, Glutathione and malonaldialdehyde (MDA). Protein expression studies of pro and anti apoptotic markers were carried out to elucidate their possible involvement in diabetic context.

Results

SOD and MDA activity was significantly higher in the lymphocytes of diabetic patients having chronic, non healing diabetic wound as compared with healthy (p < 0.001); whereas catalase and GSH activity was significantly reduced (p < 0.001) in the same group. Expressions of pro apoptotic markers (Caspase-3, Fas and Bax) were significantly higher whereas reduced expression of anti-apoptotic marker (Bcl-2) were obtained in lymphocytes of diabetic and non diabetic individuals.

Conclusions

Hyperglycemia confers pro apoptotic manifestations which are mostly through altered indices of oxidative stress within lymphocytic milieu.     

Potential celiac disease in type 1 diabetes: a multicenter study

Aims

To describe the prevalence of potential celiac disease (pot-CD) in young patients with type 1 diabetes mellitus (T1DM) and characterize their clinical features.

Methods

This cross-sectional multicenter study involved 8717 T1DM patients from 31 Italian centers. Information was collected on the total number of T1DM patients, CD patients and pot-CD patients. The following data were collected on pot-CD patients: gender, age at T1DM diagnosis, age at the first CD serological positivity, presence of CD-related symptoms, presence of other autoimmune disorders and treatment with gluten free diet (GFD). One thousand-three-hundred-sixty-one patients who were positive for CD serology were the control group.

Results

CD serological positivity was found in 7.2% T1DM patients. Prevalence of pot-CD was 12.2% (n = 77) among CD positive patients: symptoms were present in 12/77; a third autoimmune disorder was found in 15 patients. Prevalence of pot-CD in the control population was 8.4% (n = 114; p = 0.005). No difference was found with regard to clinical features. Only few symptomatic patients were on GFD both in T1DM and control patients.

Conclusions

A higher prevalence of pot-CD was found in T1DM patients, that may be ascribed to the routine screening, although the influence of genetic factors cannot be excluded.     

Association between serum soluble TNFα receptors and renal dysfunction in type 2 diabetic patients without proteinuria

Aim

The aim of our study was to investigate whether serum levels of soluble tumor necrosis factor α receptor (sTNFR) 1 and 2 are markers for renal dysfunction in type 2 diabetic patients without overt proteinuria.

Methods

Japanese type 2 diabetic patients without overt proteinuria (n = 168) enrolled in the prospective observational follow-up study in 2001 were retrospectively analyzed. At baseline, the serum levels of sTNFR1 and sTNFR2 were measured by sandwich ELISA. The associations between these markers and change in estimated glomerular filtration rate (eGFR) after 5 years were evaluated.

Results

The levels of sTNFR1 and sTNFR2 closely correlated. At baseline, sTNFR1 and sTNFR2 associated inversely with eGFR. After 5 years, patients with high level of both sTNFR1 and sTNFR2 showed a greater decline in eGFR (−13.8 ± 15.5% versus −8.5 ± 11.8%, P = 0.027) and a 4-fold higher risk for a GFR decline of ≥25% than those with high level of only one receptor or low level of both receptors. These associations were enhanced in diabetic women.

Conclusions

The higher levels of sTNFR1 and sTNFR2 were associated with a greater decline in eGFR in type 2 diabetic patients without proteinuria, especially in diabetic women.     

The foot in type 2 diabetes: is there a link between vascular calcification and bone mineral density?

Aims

To examine the relationship between vascular calcification in the foot (FVC) and bone mineral density (BMD) in the heel of type 2 diabetes mellitus (DM) subjects.

Methods

65 subjects with type 2 DM and serum creatinine < 125 μmol/l underwent CT scanning of the foot to assess FVC and dual energy X ray absorptiometry (DEXA) scan to assess heel BMD. Routine biochemistry including osteoprotegerin (OPG) and Receptor activator of nuclear factor kappa-B ligand (RANKL) was also carried out.

Results

The proportion of subjects with FVC was 43%, whilst 40% had low BMD (T score < −1.0). Age, neuropathy and 25 hydroxyvitamin D were independent predictors of FVC. Body-weight, eGFR, 25 hydroxyvitamin D, OPG, and total cholesterol were independent predictors of low heel BMD. There was no correlation between albuminuria and BMD or FVC. There was no difference in heel BMD between those with FVC and those without, but those with frank osteoporosis were significantly more likely to have FVC than those with higher BMD.

Conclusions

There is no clear-cut association between FVC and low BMD in type 2 DM with relatively well-preserved renal function. Age, neuropathy, eGFR, hyperlipidemia, body-weight, 25 hydroxyvitamin D and OPG play a complex role in their pathogenesis.     

NSAID use and progression of chronic kidney disease

Purpose

The effects of nonselective and selective cyclooxygenase-2 specific (COX-2) nonsteroidal anti-inflammatory drug (NSAID) use on the progression of chronic kidney disease (CKD) is uncertain. Due to the high prevalence of both CKD and NSAID use in older adults, we sought to determine the association between NSAID use and the progression of CKD in an elderly community-based cohort.

Methods

All subjects ≥66 years of age who had at least one serum creatinine measurement in 2 time periods (July-December, 2001 and July-December, 2003) were included. Multiple logistic regression analyses, including covariates for age, sex, baseline estimated glomerular filtration rate (eGFR), diabetes, and comorbidity were used to explore the associations of NSAID use on the primary (decrease in eGFR of ≥15 mL/min/1.73²) and secondary (mean change in eGFR) outcomes.

Results

A total of 10,184 subjects (mean age 76 years; 57% female) were followed for a median of 2.75 years. High-dose NSAID users (upper decile of cumulative NSAID exposure) experienced a 26% increased risk for the primary outcome (odds ratio [OR] 1.26, 95% confidence interval [CI], 1.04-1.53). A linear association between cumulative NSAID dose and change in mean GFR also was seen. No risk differential was identified between selective and nonselective NSAID users.

Conclusions

High cumulative NSAID exposure is associated with an increased risk for rapid CKD progression in the setting of a community-based elderly population. For older adult patients with CKD, these results suggest that nonselective NSAIDs and selective COX-2 inhibitors should be used cautiously and chronic exposure to any NSAID should be avoided.     

Utilization patterns and cost of complementary and alternative medicine compared to conventional medicine in patients with type 2 diabetes mellitus

Aims

We evaluated the use and annual cost of complementary and alternative medicine (CAM) compared to conventional medicine in type 2 diabetes mellitus (DM) in the Korean population.

Methods

We analyzed the database of 2752 DM patients obtained from the Korean National Diabetes Program (KNDP). The cost data of conventional medicine starting 1-year before enrolment of the KNDP were obtained from the hospital electronic database. The cost data of CAM over the same period were obtained from questionnaires.

Results

Among the 2752 subjects, 677 patients (24.6%) used CAM, with the most common type being red ginseng and herbal medicine. Patients with a higher income, neuropathy, and self-monitoring of blood glucose (SMBG) were more likely to use CAM. Men, those with a higher education level and income, no cerebrovascular accident (CVA) history, and SMBG showed a relatively higher cost of CAM of total medical cost. The independent predictors for CAM were a higher income, the existence of diabetic neuropathy, no CVA history, and SMBG.

Conclusions

Use and cost of CAM varied depending on income, accompanying complications and SMBG. To evaluate the total medical costs in DM patients, a comprehensive approach considering not only conventional cost but also CAM is required.     

Urinary Kidney Injury Molecule-1 and the Risk of Cardiovascular Mortality in Elderly Men

Background and objectives

Kidney injury molecule-1 (KIM-1) has been suggested as a clinically relevant highly specific biomarker of acute kidney tubular damage. However, community-based data on the association between urinary levels of KIM-1 and the risk for cardiovascular mortality are lacking. This study aimed to investigate the association between urinary KIM-1 and cardiovascular mortality.

Design, setting, participants, & measurements

This was a prospective study, using the community-based Uppsala Longitudinal Study of Adult Men (N=590; mean age 77 years; baseline period, 1997–2001; median follow-up 8.1 years; end of follow-up, 2008).

Results

During follow-up, 89 participants died of cardiovascular causes (incidence rate, 2.07 per 100 person-years at risk). Models were adjusted for cardiovascular risk factors (age, systolic BP, diabetes, smoking, body mass index, total cholesterol, HDL cholesterol, antihypertensive treatment, lipid-lowering treatment, aspirin treatment, and history of cardiovascular disease) and for markers of kidney dysfunction and damage (cystatin C–based eGFR and urinary albumin/creatinine ratio). Higher urinary KIM-1/creatinine (from 24-hour urine collections) was associated with a higher risk for cardiovascular mortality (hazard ratio per SD increase, 1.27; 95% confidence interval [95% CI], 1.05 to 1.54; P=0.01). Participants with a combination of high KIM-1/creatinine (upper quintile, ≥175 ng/mmol), low eGFR (≤60 ml/min per 1.73 m²), and microalbuminuria/macroalbuminuria (albumin/creatinine ratio≥3 g/mol) had a >8-fold increased risk compared with participants with low KIM-1/creatinine (<175 ng/mmol), normal eGFR (>60 ml/min per 1.73 m²), and normoalbuminuria (albumin/creatinine ratio<3 g/mol) (hazard ratio, 8.56; 95% CI, 4.17 to 17.56; P<0.001).

Conclusions

These findings suggest that higher urinary KIM-1 may predispose to a higher risk of cardiovascular mortality independently of established cardiovascular risk factors, eGFR, and albuminuria. Additional studies are needed to further assess the utility of measuring KIM-1 in the clinical setting.     

Dietary salt restriction increases plasma lipoprotein and inflammatory marker concentrations in hypertensive patients

Background

Dietary salt restriction has been reported to adversely modify the plasma lipoprotein profile in hypertensive and in normotensive subjects. We investigated the effects of the low sodium intake (LSI) on the plasma lipoprotein profile and on inflammation and thrombosis biomarkers during the fasting and postprandial periods.

Methods

Non-obese, non-treated hypertensive adults (n = 41) were fed strictly controlled diets. An initial week on a control diet (CD, Na = 160 mmol/day) was followed by 3 weeks on LSI (Na = 60 mmol/day). At admission and on the last day of each period, the 24-h ambulatory blood pressure was monitored and blood was drawn after an overnight fasting period and after a fat-rich test meal.

Results

The dietary adherence was confirmed by 24-h urinary sodium excretion. Fasting triglyceride (TG), chylomicron-cholesterol, hsC-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) concentrations, renin activity, aldosterone, insulin, and homeostasis model assessment insulin resistance (HOMA-IR) values were higher, but non-esterified fatty acids (NEFA) were lower on LSI than on CD. For LSI, areas under the curve (AUC) of TG, chylomicron-cholesterol, apoB and the cholesterol/apoB ratio were increased, whereas AUC-NEFA was lowered. LSI did not modify body weight, hematocrit, fasting plasma cholesterol, glucose, adiponectin, leptin, fibrinogen and factor VII (FVII), and AUC of lipoprotein lipase and of lipoprotein remnants.

Conclusion

LSI induced alterations in the plasma lipoproteins and in inflammatory markers that are common features of the metabolic syndrome.     

Neutrophil Gelatinase-Associated Lipocalin and Acute Kidney Injury after Cardiac Surgery: The Effect of Baseline Renal Function on Diagnostic Performance

Background and objectives: Neutrophil Gelatinase-Associated Lipocalin (NGAL) is rapidly released by renal tubules after injury, potentially allowing early identification of acute kidney injury (AKI) after cardiac surgery. However, the diagnostic performance of NGAL has varied widely in clinical studies, and it remains unknown what factors modify the relationship between NGAL and AKI. We hypothesized the relationship between urinary NGAL and AKI would vary with baseline renal function, allowing a stratified analysis to improve diagnostic performance of this novel biomarker.Design, setting, participants, & measurements: We performed a prospective observational study in 426 adult cardiac surgical patients. Urinary NGAL was serially determined, commencing preoperatively and continuing 24 hours postoperatively. AKI was defined as increase in serum creatinine from baseline by either >50% or >0.3 mg/dl within 48 hours postoperatively. Patients were stratified by baseline estimated GFR (eGFR). NGAL levels were compared between patients with and without AKI and diagnostic characteristics determined according to baseline eGFR.Results: In patients with baseline eGFR ≥60 ml/min, urinary NGAL was higher at all postoperative time points in patients who developed AKI compared with those who did not. In patients with baseline eGFR <60 ml/min, urinary NGAL did not differ at any time between those who did and those who did not develop AKI. Postoperative NGAL best identified AKI in patients with baseline eGFR 90 to 120 ml/min.Conclusions: The relationship between urinary NGAL and AKI after cardiac surgery varies with baseline renal function, with optimal discriminatory performance in patients with normal preoperative function.Acute Kidney Injury (AKI) is a common complication after cardiac surgery, with reported incidence varying from 20% to 50% depending on the definition used (1–4). Early detection of injury is desirable to facilitate early intervention aimed at limiting associated morbidity and mortality. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is rapidly released by renal tubules in response to injury, and an acute rise in urinary NGAL has been reported to accurately identify evolving AKI in both pediatric and adult populations within 2 to 8 hours of cardiac surgery (5–9). However, other studies have found urinary NGAL to have only modest discriminant ability for AKI after cardiac surgery (3,10). Studies reporting excellent discriminant ability have generally excluded patients with preoperative renal dysfunction, whereas those studies reporting a more modest performance have included patients with a heterogeneous mix of baseline renal function. Although it is unknown whether baseline renal function modifies the relationship between NGAL and AKI, the existence of such a relationship may contribute to the limited predictive ability in these studies. Although NGAL is proposed as a real-time marker of acute renal injury rather than renal function, the nonlinear relationship between GFR and serum creatinine may mean that a relatively larger injury, producing a larger reduction in GFR, is required to cause a rise in serum creatinine sufficient to meet diagnostic criteria for AKI in a patient with normal baseline GFR. Conversely, a much smaller injury (and smaller incremental reduction in GFR) may be sufficient to cause a rise in creatinine that would diagnose AKI in a patient with impaired GFR at baseline. If true, the diagnostic utility of urinary NGAL for a creatinine-based diagnosis of AKI may be enhanced using an approach stratified by baseline renal function. We have previously reported a modest performance of urinary NGAL for early identification of evolving AKI in a large, unselected adult population undergoing cardiac surgery, with a wide range of baseline renal function. In this posthoc analysis we sought to investigate this potential source of effect modification to the relationship between NGAL and postoperative AKI. We hypothesized that the relationship between postoperative urinary NGAL and AKI would vary with baseline renal function, measured by estimated GFR (eGFR). We further hypothesized that the diagnostic performance of NGAL for postoperative AKI would be improved using an analysis stratified by baseline function, allowing the use of different diagnostic thresholds.     

Vitamin D and cognitive functioning in the elderly population in Germany

Objectives

To examine the relationship of serum 25-hydroxy vitamin D3 with cognitive functioning in higher age, using an instrument covering multiple cognitive domains in a population-based study.

Design

Follow-up study with measurement of vitamin D levels at baseline and assessment of cognitive functioning at year 5 follow-up.

Setting and participants

A subgroup of 1639 participants of the ongoing epidemiological ESTHER study of the elderly general population in Saarland State, Germany, aged 65 + years at baseline (2000-2002).

Intervention

Observational study.

Measurements

Cognitive functioning was assessed by the COGTEL phone interview developed by Kliegel et al., which was administered 5 years after ESTHER baseline. Vitamin D in baseline samples was measured by chemiluminescence methods. Additional information was obtained by standardised questionnaires.

Results

In multiple linear regression adjusted for important confounders, women in the lowest sex-specific quintile of vitamin D showed an on average 2.1 (95% confidence interval: 0.4 to 3.9) units lower COGTEL score than women in the highest quintile. A similar, albeit slightly weaker, association was seen in males (difference of 1.7 [− 0.4 to 3.8] units). Spline regression suggested non-linearity with a distinct decline in cognitive performance in the lower range of vitamin D levels.

Conclusions

Our findings support suggestions that low levels of vitamin D may be associated with reduced cognitive functioning in the elderly.     

Efficacy of urinary N-acetyl-β-D-glucosaminidase to evaluate early renal tubular damage as a consequence of type 2 diabetes mellitus: a cross-sectional study

We assessed the prognostic accuracy of urinary N-acetyl-β-D-glucosaminidase (NAG), an early proximal tubular damage marker for the onset of diabetic nephropathy. The study included 491 eligible participants with 76 healthy controls, 194 type 2 diabetes mellitus (T2DM) patients with 0–5, 5–10, 10–15, and 15–20 years of T2DM duration, 71 microalbuminuric patients, 100 diabetic nephropathy patients, and 50 non-diabetic nephropathy patients. Fasting glucose, serum fructosamine, HbA1C, urinary microalbumin, serum creatinine, estimated glomerular filtration rate (eGFR), serum NAG, and urinary NAG were estimated. We compared urinary NAG activity with other well-established markers of diabetic nephropathy like microalbuminuria, eGFR, and serum creatinine. Urinary NAG excretion was increased by 8 and 12 folds in T2DM patients of 10–15 and 15–20 years of diabetes duration (p < 0.0001), respectively, without the appearance of microalbuminuria. The urinary NAG activity increased 16 and 18 fold in moderately increased albuminuria and diabetic nephropathy patients, respectively (p < 0.0001), without any change in non-diabetic nephropathy patients. A cutoff value of 3 U/L of urinary NAG has demonstrated a sensitivity of 96.1 % and a specificity of 100 % discriminating healthy controls from patients with T2DM duration of 10–15 years (AUC 1.000) and 15–20 years (AUC 0.999); microalbuminuria (AUC 0.999), and diabetic nephropathy (AUC 1.000). Urinary NAG excretion gradually increases with the increase in duration of diabetes and appeared much before the microalbuminuria, decreased eGFR, and increased serum creatinine. Thus, the urinary NAG may be considered as a potential site-specific early tubular damage marker leading to diabetic nephropathy.

     

The Association of Inhaled Corticosteroid Use with Serum Glucose Concentration in a Large Cohort

Background

Inhaled corticosteroids (ICSs) are widely used in the treatment of obstructive lung disease. ICSs have been shown to be systemically absorbed. The association between ICS and serum glucose concentration is unknown.

Methods

To explore the association of ICS dosing with serum glucose concentration, we used a prospective cohort study of US veterans enrolled in 7 primary care clinics between December 1996 and May 2001 with 1 or more glucose measurements while at least 80% adherent to ICS dosing. The association between ICS dose from pharmacy records standardized to daily triamcinolone equivalents and serum glucose concentration was examined with generalized estimating equations controlling for confounders, including systemic corticosteroid use.

Results

Of the 1698 subjects who met inclusion criteria, 19% had self-reported diabetes. The mean daily dose of ICS in triamcinolone equivalents was 621 μg (standard deviation 555) and 610 μg (standard deviation 553) for subjects with and without diabetes, respectively. After controlling for systemic corticosteroid use and other potential confounders, no association between ICS and serum glucose was found for subjects without diabetes. However, among subjects with self-reported diabetes, every additional 100 μg of ICS dose was associated with an increased glucose concentration of 1.82 mg/dL (P value .007; 95% confidence interval [CI], 0.49-3.15). Subjects prescribed antiglycemic medications had an increase in serum glucose of 2.65 mg/dL (P value .003; 95% CI, 0.88-4.43) for every additional 100 μg ICS dose.

Conclusion

Among diabetic patients, ICS use is associated with an increased serum glucose concentration in a dose-response manner.