High levels of oxidized LDL in circulating immune complexes are associated with increased odds of developing abnormal albuminuria in Type 1 diabetes (original) (raw)
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International journal of endocrinology, 2012
Oxidized low density lipoprotein (ox-LDL) is a product of oxidative stress. In this cross-sectional study, we compared the ox-LDL concentrations in diabetic patients with normoalbuminuria (n = 28), microalbuminuria (n = 28), and macroalbuminuria (n = 28) with their first degree relatives (n = 28) and healthy control people (n = 31). They were selected by consecutive patient selection method. The ox-LDL level was assayed using ELISA. We measured blood pressure, lipid profile, fasting plasma glucose (FPG), and HbA1c in all groups. There was no significant difference in ox-LDL concentrations among normoalbuminuric, microalbuminuric, and macroalbuminuric diabetic groups. In diabetic patients with micro- and macroalbuminuria, ox-LDL concentration was higher than their first degree relatives (P = 0.04 and P = 0.03) and control group (P = 0.001 and P = 0.03, resp.). In normoalbuminuric diabetic persons, ox-LDL concentration was just higher than that of healthy people (P = 0.02). There was ...
Albuminuria Changes and Cardiovascular and Renal Outcomes in Type 1 Diabetes: The DCCT/EDIC Study
Clinical Journal of the American Society of Nephrology, 2016
Background and objectives In trials of people with type 2 diabetes, albuminuria reduction with renin-angiotensin system inhibitors is associated with lower risks of cardiovascular events and CKD progression. We tested whether progression or remission of microalbuminuria is associated with cardiovascular and renal risk in a well characterized cohort of type 1 diabetes. Design, setting, participants, & measurements We studied 1441 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Albumin excretion rate (AER) was quantified annually or biennially for up to 30 years. For each participant, albuminuria status was defined over time as normoalbuminuria (AER continuously ,30 mg/d), sustained microalbuminuria (AER, 30-299 mg/d on two consecutive visits), macroalbuminuria (AER$300 mg/d), or remitted microalbuminuria (transition from sustained microalbuminuria to AER,30 mg/d on two consecutive visits). We tested associations of time-updated albuminuria status with adjudicated clinical cardiovascular events, the development of reduced GFR (,60 ml/min per 1.73 m 2 on two consecutive visits), and subclinical cardiovascular disease. Results At least one cardiovascular event occurred in 184 participants, and 98 participants developed reduced eGFR. Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were each associated with higher risk of cardiovascular events (adjusted hazard ratios [HRs] and 95% confidence intervals [95% CIs]: 1.79 [1.13 to 2.85], 2.62 [1.68 to 4.07], and 2.65 [1.68 to 4.19], respectively) and reduced eGFR (adjusted HRs [95% CIs], 5.26 [2.43 to 11.41], 4.36 [1.80 to 10.57], and 54.35 [30.79 to 95.94], respectively). Compared with sustained microalbuminuria, remission to normoalbuminuria was not associated with reduced risk of cardiovascular events (adjusted HR, 1.33; 95% CI, 0.68 to 2.59) or reduced eGFR (adjusted HR, 1.75; 95% CI, 0.56 to 5.49). Compared with normoalbuminuria, sustained microalbuminuria, remitted microalbuminuria, and macroalbuminuria were associated with greater carotid intima-media thickness, and macroalbuminuria was associated with a greater degree of coronary artery calcification. Conclusions In type 1 diabetes, microalbuminuria and macroalbuminuria are associated with higher risks of cardiovascular disease and reduced eGFR, but achieving a remission of established microalbuminuria to normoalbuminuria does not appear to improve outcomes.
Nephrology Dialysis Transplantation, 2008
Background. It is uncertain whether albuminuria precedes the future development of high total cholesterol (TC > 6.2 mmol/l) and high LDL-C (>4.1 mmol/l) while renal dysfunction precedes the future development of low HDL-C (<0.9 mmol/l) in type 2 diabetes. Methods. A prospective cohort of 2761 type 2 diabetic patients without significant dyslipidaemia and having at least one measurement of TC, LDL-C and HDL-C during 2.8 years of follow-up was analysed. The spline Cox regression model was used to derive hazard ratio (HR) curves of the spot urinary albumin:creatinine ratio (ACR) and the estimated glomerular filtration rate (eGFR) for dyslipidaemia, followed by standard Cox models to confirm the findings from the HR curves. Results. Seven percent of the cohort developed high TC, 4.6% developed high LDL-C and 5.7% developed low HDL-C during follow-up. In multivariate analysis, the HR of ACR for high TC and high LDL-C increased rapidly and linearly from zero with no apparent threshold. Patients with macroalbuminuria (ACR ≥25 mg/mmol) were, respectively, 1.6-and 2.4 folds more likely to develop high TC and high LDL-C than those with normoalbuminuria at baseline. The HR of eGFR for low HDL-C increased rapidly with declining eGFR at <110 ml/min/ 1.73 m 2 . Subjects with eGFR <60 ml/min/1.73 m 2 and ≥60-<110 ml/min/1.73 m 2 , respectively, had 3.0-fold and 1.8-fold risks of low HDL-C compared to those with eGFR ≥110-<140 ml/min/1.73 m 2 . Conclusions. In type 2 diabetes, macroalbumninuria predicts high TC and high LDL-C, while reduced renal function, even within normal range, predicts low HDL-C.
International Urology and Nephrology, 2010
The pathogenesis of diabetic nephropathy, mainly characterized by macroalbuminuria, is still poorly understood, but it is reported that transforming growth factor-b (TGF-b) plays a key role. In vitro evidence suggests that administration of oxidized LDL (ox-LDL) can lead to upregulation of TGF-b by human glomerular mesangial cells. This study aimed to evaluate the association between macroalbuminuria, ox-LDL, and TGF-b in diabetic patients. A total of 77 type 2 diabetic patients with macroalbuminuria (albumin excretion rate: AER C 300 mg/24 h) and 66 patients with normoalbuminuria (AER B 30 mg/ 24 h) were recruited. Fasting blood samples were obtained and serum levels of ox-LDL and TGF-b were determined. Ox-LDL and TGF-b were significantly higher in patients with macroalbuminuria than in those with normoalbuminuria (98.93 ± 3.99 vs. 72.45 ± 2.48 U/l; P \ 0.001 and 6.46 ± 0.74 vs. 2.49 ± 0.39 ng/ml; P \ 0.001, respectively). In patients with macroalbuminuria, there was a significant correlation between Ox-LDL and TGF-b (r = 0.376; P \ 0.01). AER was significantly correlated to ox-LDL (r = 0.302; P \ 0.05) and TGF-b (r = 0.306; P \ 0.05) in macroalbuminuric patients. This association remained significant after adjustment for potential confounders. Adjustment for TGF-b (ox-LDL), attenuated the association of ox-LDL (TGF-b) with AER. In conclusion, this study demonstrated the association of TGF-b and ox-LDL with albuminuria in macroalbuminuric type 2 diabetic patients, and suggested that this relationship is highly mediated through the correlation between TGF-b and ox-LDL.
Diabetes Care
OBJECTIVE The current study aimed to determine in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications cohort whether or not abnormal levels of markers of inflammation and endothelial dysfunction measured in samples collected at DCCT baseline were able to predict the development of macroalbuminuria.RESEARCH DESIGN AND METHODS Levels of inflammation and endothelial cell dysfunction biomarkers were measured in 1,237 of 1,441 patients enrolled in the DCCT study who were both free of albuminuria and cardiovascular disease at baseline. To test the association of log-transformed biomarkers with albuminuria, generalized logistic regression models were used to quantify the association of increased levels of biomarkers and development of abnormal albuminuria. Normal, micro-, and macroalbuminuria were the outcomes of interest.RESULTSIn the logistic regression models adjusted by DCCT treatment assignment, baseline albumin excretion rate, ...
Iranian Red Crescent Medical Journal, 2016
Background: The globally increasing epidemic of diabetes will lead to serious problems including diabetic nephropathy and kidney diseases in near future. The first clinical diagnosable stage in a diabetic kidney disease is microalbuminuria (urinary albumin excretion of 30-300 g/24 hours). Objectives: This prospective cohort study investigated the risk factors of microalbuminuria in patients with type 2 diabetes who had been registered in endocrine and metabolism research center in Isfahan city, Iran. Patients and Methods: This prospective cohort study was performed on 90 diabetic type 2 patients with microalbuminuria, who were selected according to the consecutive sample selection method during 6 years. Data were collected through regular and systematic measurements of serum albumin as the response variable and body mass index, systolic and diastolic blood pressure, the duration of diabetes, glycosylated hemoglobin (HbA1c), total cholesterol, triglyceride (TG), fasting blood sugar (FBS), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) as the related factors. Non-normal mixed models were used to investigate the impact of effective factors on the amount of excreted serum albumin. Results: According to the deviance information criterion (DIC = 56.2), the non-normal mixed effects model with the skewed t distribution had a best fit and indicated that HbA1c, HDL and total cholesterol had a significant effect on the amount of albumin in urine (P < 0.05). Conclusions: Using nonnormal mixed models may lead to the best results as compared to common normality assumption.
Clinical Immunology, 2008
Modified lipoproteins are immunogenic and play a key pathogenic role in vascular disease. Antibodies to oxidized LDL (oxLDL) are mostly of the proinflammatory IgG 1 and IgG 3 isotypes. We measured IgG and IgM oxLDL antibodies in immune complexes (IC) isolated from 36 patients with type 1 diabetes using a nested case-control design. IgG antibodies predominated over IgM antibodies by an 8:1 ratio. IgG antibody concentrations were higher in the nephropathy cases compared to controls (p=0.09), but no significant difference was observed because of two patients included in the study who had end-stage renal disease (creatinine > 5mg/dl and glomerular filtration rate (GFR) less than 17 ml/min). After eliminating these patients from the analysis, significant positive associations of IgG antibody concentration with serum creatinine and albumin excretion rate were observed after eliminating two patients with significant renal impairment (serum creatinine > 5 mg/dl). Similarly, a negative correlation with estimated glomerular filtration rate was observed in this subsample of 34 patients. Differences in IgM antibody concentrations by nephropathy classification were not supported by the data. In conclusion, the predominance of pro-inflammatory IgG oxLDL antibodies is associated with existence of diabetic nephropathy, and a protective role of IgM antibodies could not be demonstrated.
American Journal of Kidney Diseases, 2006
Background: Microalbuminuria is an independent risk factor for cardiovascular morbidity and mortality in the general population. Standard immunochemical urinary albumin assays detect immunoreactive albumin, whereas high-performance liquid chromatography (HPLC) detects both immunoreactive and immunounreactive albumin. Methods: Using data from the Australian Diabetes, Obesity, and Lifestyle cohort study of randomly selected communitybased Australian adults, spot urine samples were tested for albuminuria (spot urine albumin-creatinine ratio [ACR]: normal, <30 mg/g; microalbuminuria, 30 to 300 mg/g; and macroalbuminuria, >300 mg/g) by using both immunonephelometry IN) and HPLC (n ؍ 10,010). Results: Bland-Altman analysis showed significant bias, with a greater ACR by means of HPLC, particularly at lower levels of ACR. Mean ACR was 15.8 mg/g (95% confidence interval [CI], 12.3 to 19.2) by means of IN compared with 30.0 mg/g (95% CI, 27.0 to 35.0) by means of HPLC. The prevalence of microalbuminuria was 4 times greater by means of HPLC compared with IN (20% versus 5.5%). In all demographic and comorbid subgroups associated with microalbuminuria, the prevalence of microalbuminuria increased by 2 to 4 times. A total of 1,743 subjects (17.4%) classified as normoalbuminuric by means of IN were reclassified as microalbuminuric by means of HPLC. Using multivariate logistic regression, women, patients with untreated and treated hypertension, and those with impaired glucose tolerance or diabetes were associated significantly with a change in category from normoalbuminuric to microalbuminuria by means of HPLC. Conclusion: HPLC measures significantly more urinary albumin within the normoalbuminuria and microalbuminuria range, resulting in a significant increase in prevalence of microalbuminuria. Longitudinal studies are needed to determine whether the extra individuals identified by means of HPLC are at increased risk for developing hard clinical outcomes (renal and cardiovascular). Am J Kidney Dis 47:604-613.
Diabetes Care, 1993
OBJECTIVE-To examine the relationships between microalbuminuria and the development of overt diabetic nephrology, elevated blood pressure, and a more atherogenic lipid profile; and to identify risk factors for the development of microalbuminuria in individuals with IDDM. Microalbuminuria has been associated with the subsequent development of overt diabetic nephropathy in individuals with IDDM. It is associated with elevated blood pressure and a more atherogenic lipid profile, but the temporal relationship between the development of microalbuminuria and the changes in these factors is unclear.